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 Julie Rees - Link between LDL, insulin resistance, and diet

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 Julie Rees - Link between LDL, insulin resistance, and diet

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We know that a specific diet will not work for everyone.  This diet compared three low saturated fat diets and compared how they affected LDL levels in patients with low and high insulin resistance.  They used the DASH diet plus Beef in an Optimal Lean Diet (BOLD) and BOLD+ which adds addition protein sources to the BOLD diet.  The Healthy American diet (HAD) with higher saturated fat intake was used as the control.  In patients with low insulin resistance, a decrease in LDL of about 12% was seen in all 3 diets.  However, in patients with high insulin resistance, the diets gave mixed results.  BOLD+ showed a LDL decrease of 11% while BOLD showed no change.  Interestingly, the DASH diet increased patient LDL levels by 6%.

This study highlights the importance of adjusting lifestyle changes to find a treatment that best suits the patient.  We also need to be aware that we need to treat the entire patient and not hyperfocus on one condition without considering the effects of comorbidities.

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Baseline Insulin Resistance Is a Determinant of the Small, Dense Low-Density Lipoprotein Response to Diets Differing in Saturated Fat, Protein, and Carbohydrate Contents - PubMed

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Individual responses to diet vary but causes other than genetics are poorly understood. This study sought to determine whether baseline values of homeostasis model assessment (HOMA-IR) was related to changes in small, dense low-density lipoprotein (sdLDL, i.e., LDL₄, d = 1.044-1.063 g/mL)…

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SGLT2 inhibition reduces atherosclerosis by enhancing lipoprotein clearance in Ldlr−/− type 1 diabetic mice

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SGLT2 inhibition reduces atherosclerosis by enhancing lipoprotein clearance in Ldlr−/− type 1 diabetic mice

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One of the biggest risk factors for atherosclerotic cardiovascular disease is diabetes. Hyperglycemia, free fatty acids, advance glycation end product (AGE) formation, and lipoprotein oxidation correlate with inflammation and atherosclerosis. Sodium-glucose co-transport-2 inhibition (SGLT2i), a glucose inhibiting agent, showed positive outcomes for CVD. When mice were treated with SGLT2i, their lipid profiles were lowered, atherosclerotic lesions and free floating myeloid cells were reduced as well.  Mice were fed a high fat diet while being treated to stimulate a western diet and it still showed good outcomes in reducing lipoprotein clearance and reducing the chances of cardiovascular disease and heart events.

This study is important clinically because they showed that in diabetes patients, tighter glycemic control is necessary for lipoprotein clearance and reduction in atherosclerosis. They showed this clearance of lipoprotein was exclusive of Ldlr, acting via bile acid pathways and mediated by heparin sulfate proteoglycans. Nutrition is critical in managing diabetes and the other diseases that come along with it. Finding new correlations in what we eat and how our bodies interact with it is important for helping find new approaches to treatment for disease.

Stephen Mayer

Al-Sharea, A., Murphy, A. J., Huggins, L. A., Hu, Y., Goldberg, I. J., & Nagareddy, P. R. (2018). SGLT2 inhibition reduces atherosclerosis by enhancing lipoprotein clearance in Ldlr-/- type 1 diabetic mice. Atherosclerosis, 271, 166–176. https://doi.org/10.1016/j.atherosclerosis.2018.02.028

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Atherosclerosis. Author manuscript; available in PMC 2020 May 3.

Published in final edited form as:

Annas Al-Sharea, 2,^ Andrew J. Murphy, 1, 2,^ Huggins LA, 1, ³ Hu Y, 1, ³ Ira J. Goldberg, 1, ³ and Prabhakara R Nagareddy 1, 4,*

Abstract

Background and aims:

Leukocytosis, particularly monocytosis, has been shown to promote atherosclerosis in both diabetic and non-diabetic mouse models. We previously showed that hyperglycemia independently promotes monocytosis and impairs the resolution of atherosclerosis. Since patients with chronic diabetes often develop dyslipidemia and also have increased risk for atherosclerosis, we sought to examine how controlling blood glucose affects atherosclerosis development in the presence of severe hyperlipidemia.

Methods:

Diabetes was induced using streptozotocin (STZ) in low density lipoprotein receptor (Ldlr) knockout ( Ldlr−/−) mice after which they were fed a high-cholesterol diet for 4 weeks. Control and diabetic mice were treated with vehicle or sodium glucose cotransporter inhibitor (SGLT2i, Phlorizin or Dapagliflozin) for the duration of the diet.

Results:

Induction of diabetes resulted in a dramatic increase in plasma cholesterol (TC) and triglyceride (TG) levels. These mice also exhibited an increased number of circulating monocytes and neutrophils. Monocytosis was driven by increased proliferation of progenitor cells in the bone marrow. Tighter glycemic control by SGLT2i treatment not only reduced monocytosis and atherosclerosis but also improved plasma lipoprotein profile. Interestingly, improved lipoprotein profile was not due to decreased TG synthesis or clearance via low density lipoprotein receptor-related protein (Lrp) 1 or scavenger receptor class B member (Scarb1) Pathways, but likely mediated by heparin sulfate proteoglycans (HSPG)-dependent clearance mechanisms in the liver. Further examination of the liver revealed an important role for bile acid transporters (Abcg5, Abcg8) and cytochrome P450 enzymes in the clearance of hepatic cholesterol.

Conclusions:

These data suggest that tighter glycemic control in diabetes can improve lipoprotein clearance exclusive of Ldlr, likely via HSPG and bile acid pathways and, has an overall net positive effect on atherosclerosis.

1. Introduction

Diabetes is one of the most potent risk factors for atherosclerotic cardiovascular disease (CVD). Additionally, patients with CVD and diabetes are, some of the most vulnerable subjects, who suffer from recurrent cardiac events [ 1]. Whether this is due to changes in atherogenesis secondary to hyperglycemia, hyperlipidemia or other vascular toxicities such as defective insulin action is still a subject of intense debate [ 2]. Animal models linking diabetes with atherosclerosis have been studied for decades but these studies are complicated due to associated changes in plasma lipids [ 2, 3] that sometimes mask any direct effects of hyperglycemia on mouse arteries. Moreover, lipids themselves might have a number of untoward effects such as causing greater lesional hemorrhage, a finding in diabetic mice that was reduced by correction of hypertriglyceridemia [ 4]. Diabetic models created using streptozotocin (STZ) or viral destruction of islets [ 3] have both hyperglycemia and insulin deficiency, each of which may have effects on vascular cells and inflammation [ 5]. For example, lack of insulin receptors in myeloid cells reduced atherosclerosis in Apoe−/− mice, a finding associated with decreased cellular inflammation [ 6]. In contrast, endothelial insulin receptor deficiency increased atherosclerosis [ 7]. Similarly, hyperglycemia alone [ 8] or in combination with free fatty acids [ 9], lipoprotein oxidation [ 10] and advanced glycation end product (AGE) formation [ 11, 12] promotes inflammation, and in some cases correlates with more severe forms of atherosclerosis. Thus, in the setting of diabetes at least three major changes in whole body metabolism; hyperglycemia, reduced insulin actions, and hyperlipidemia, are involved in atherosclerosis [ 2].

The Diabetes Control and Complications Trial (DCCT)/Epidemiology of Diabetes Interventions and Complications (EDIC) is a landmark study that specifically examined the effects of hyperglycemia on vascular disease in type I diabetes (T1D) and over the years has convincingly demonstrated that tighter glucose control favorably alters macrovascular disease independent of changes in blood pressure or lipids [ 13]. Furthermore, in a recent clinical trial investigating the effects of sodium-glucose co-transport-2 inhibition (SGLT2i), there was a significant improvement in CVD [ 14, 15]. In line with this clinical study, we and others also reported that in animal models of T1D, hyperglycemia alone can impair the resolution of atherosclerosis either by enhancing the production of monocytes and/ or adversely affecting the polarization of lesional macrophages [ 16, 17]. However, these studies were conducted mainly in the context of atherosclerotic lesion regression and did not address the other important clinical scenario of lesion progression, which is mainly influenced by dyslipidemia [ 18] and hyperglycemia [ 3].

Mice with a genetic deficiency of LDL receptors ( Ldlr−/−) coupled with a high cholesterol-rich diet allow sufficient hyperlipidemia for development of atherosclerotic lesions [ 3, 19]. A seminal study by Bornfeldt group examining the specific role of diabetes and diabetes-associated lipid abnormalities in Ldlr−/− mice found distinct effects on the initiation and progression of atherosclerosis [ 3]. Diabetes in Ldlr−/− mice fed a cholesterol-free diet caused both accelerated lesion initiation and increased macrophage burden [ 20]. On the other hand, diabetic mice fed with cholesterol-rich diet displayed severe hypercholesterolemia and advanced lesions, suggesting that diabetes-induced dyslipidemia could accelerate atherosclerosis towards a more advanced and severe phenotype. Hyperlipidemic diabetic and non-diabetic mice with similar plasma cholesterol levels demonstrated a comparable level of atherosclerosis [ 21]. Thus, it appeared that the severe hyperlipidemia was able to swamp out hyperglycemia-driven progression of atherosclerosis.

Ldlr−/− mice display severe hypercholesterolemia in the setting of islet destruction when fed with a high cholesterol diet [ 3, 19]. The reasons for this are not clear but could reflect either or a combination of the following; A) reduced lipoprotein clearance pathways through LDL receptor-related protein (Lrp) and/ or scavenger receptors; B) increased lipoprotein production; C) reduced liver trapping associated with reduced heparan sulfate proteoglycan production (HSPG) [ 2, 20, 22]. In order to examine the factors associated with diabetes-mediated hypercholesterolemia, we created diabetes in Ldlr−/− mice using STZ and studied the effect of glucose reduction using sodium glucose cotransporter inhibitors (SGLT, phlorizin or dapagliflozin) on dyslipidemia and the ensuing atherosclerosis. Currently, there is a lack of information as to how this class of drugs can alter atherogenesis via altered lipid metabolism. In light of this, we specifically focused on the mechanisms involved in lipoprotein clearance by HSPGs because we previously had observed that decreased sulfation of HSPGs by N-deacetylase/ N-sulfotransferase-1 (Ndst1) was associated with defective lipoprotein clearance in Ldlr−/− mice with STZ-diabetes [ 20]. We hypothesized that maintenance of euglycemia preserves the function of hepatic HSPGs and thus improved clearance of lipoproteins in Ldlr−/− mice with T1D.

2. Materials and methods

2.1. Animals

Male, 10-12 week old Ldlr−/− (B6.129S7-Ldlr tm1Her) mice on C57BL6 background were purchased from The Jackson Laboratory. Mice were maintained in a temperature-controlled (25°C) facility with a 12-h light/dark cycle and given free access to food and water, except when fasting blood specimens were obtained. Diabetes was induced by streptozotocin (STZ) according to the AMDCC protocol (50 mg/kg body weight intraperitoneally for 5 days) and one week after the last injection of STZ, the Ldlr−/− mice were placed on a cholesterol rich diet (0.15% cholesterol; catalog no. D01061401; Research Diets Inc.,) for 4 weeks. Phlorizin treatment was started on the same day of diet. Phlorizin was administered subcutaneously at a dose of 400 mg/kg/ twice daily for 4 weeks [ 23]. A group of control and diabetic mice received vehicle (10% DMSO, 15% alcohol and 75% saline). In a separate study, diabetic and non-diabetic Ldlr−/− mice on cholesterol rich diet were treated with dapagliflozin, a specific SGLT2 inhibitor at 25 mg/kg b.w for 4 weeks in drinking water. Unless indicated, reversal of hyperglycemia was achieved mainly by using phlorizin. All protocols were approved by the Animal Care and Use Committee of Columbia University and followed the Guide for the Care and Use of Laboratory Animals.

2.2. Metabolic and vascular characterization

Mice were caged individually and treated with either phlorizin or vehicle, as described above. The amount of food in the feeding container was measured once every 2 days. Food intake was normalized to body weight of each mouse and was expressed as g/ day. Plasma samples were obtained from 6-h-fasted mice. Blood glucose was measured directly from the tail tip using a One Touch Ultra 2 glucose monitoring system (Lifescan, Johnson & Johnson, USA). Total cholesterol and triglycerides (TG) levels in the plasma were measured using colorimetric assays (Wako Diagnostics). Plasma insulin was measured by ELISA (using kits from ALPCO Immunoassays) as per the manufacturer's instructions. For lipoprotein analysis, VLDL [density 1.006 g/ml], intermediate-density lipoprotein plus LDL [density 1.006-1.063 g/ml], and HDL [density 1.063-1.21 g/ml], were separated by sequential density ultracentrifugation of plasma in a TLA100 rotor (Beckman Coulter, Brea, CA, USA) followed by colorimetric analysis of cholesterol and TG levels. For atherosclerotic lesion analysis, serial frozen sections of proximal aortic roots were prepared and stained with H&E for quantification of lesion size as previously described [ 17]. Oil Red O staining was employed for lipid quantification while CD68 staining was used to assess macrophages in lesions of the proximal aortic root. En face analysis was performed to quantify lipids in atherosclerotic plaques of aortic arch. Quantification was performed using either Image J, Image Pro Plus or Adobe Photoshop CS5.

2.3. Flow cytometry

For identification of monocytes and neutrophils from whole blood the following strategy was employed. Blood was drawn via tail bleeding and collected into EDTA lined tubes and immediately placed on ice. All following steps were performed on ice. RBCs were lysed (BD PharmLyse, BD Bioscience) and WBCs were centrifuged, washed and resuspended in HBSS (0.1% BSA w/v, 5mM EDTA). Cells were stained with a cocktail of antibodies against CD45-APC-Cy7, Ly6-C/G-PerCP-Cy5.5 (BD Pharmigen), CD115-APC and CD11b-FITC (eBioscience). Samples were analyzed on an LSR-II (BD Biosciences) flow cytometer. Monocytes were identified as CD45 hiCD115 hi and further classified into Ly6-C hi and Ly6-C lo subsets. Neutrophils were identified as CD45 hiCD115 loLy6-C/G hi (Gr-1). The mean fluorescence intensity of CD11b on the surface of monocytes and neutrophils was measured as marker of activation [ 17, 24]. Total WBC counts were obtained from freshly drawn blood via tail bleeding and quantified using the FORCYTE Veterinary Analyzer (Oxford Science Inc, Oxford, CT, USA). For identification of BM HSPCs, bone marrow was harvested from the femurs and tibias by flushing with ice cold PBS on a 40-μm cell strainer over a 50-ml centrifuge and subjected to brief RBC lysis. BM was suspended in HBSS (BSA/ EDTA) and incubated with a cocktail of antibodies to lineage committed cells (CD45R, CD19, CD11b, CD3e, TER-119, CD2, CD8, CD4, Ly-6G: All FITC, eBioscience), Sca1-Pacific Blue, ckit-APC Cy7. Where further identification of progenitor subsets was required, antibodies to CD16/CD32 (FcγRII/III), CD34 to separate CMP (lin −, Sca1 −, ckit⁺, CD34 int, FcγRII/III int), GMP (lin −, Sca1 −, ckit⁺, CD34 int, FcγRII/III hi) and MEP (lin −, Sca1 −, ckit⁺, CD34 lo, FcγRII/III lo). HSPCs were identified as lin −, Sac1⁺ and ckit⁺ cells and analyzed using LSRII flow cytometer (BD Biosciences, NJ, USA) with FACS DiVa software. Data were analyzed using FlowJo software (Tree Star Inc.) For identification of HSPCs in the splenic tissues, spleens were weighed and minced into small pieces using a pair of scissors followed by manual disruption on a 40-μm cell strainer over a 50-ml centrifuge tube using a syringe piston. The single cell suspension was washed with PBS and cells collected via centrifugation (300g, 5 min) and subject to a brief RBC lysis. HSPCs and progenitor cells were analyzed by flow cytometry as described above.

2.4. Tissue collection, RNA isolation, cDNA synthesis, qRT-PCR and Western blotting

When the mice were killed, hearts were perfused with 10 ml ice cold PBS. Adequacy of the perfusion was evident from blanching of the livers. Tissues were removed and immediately frozen in liquid nitrogen. Total RNA from BM and liver was extracted using RNeasy Micro kit (Qiagen) and cDNA synthesized using SuperScript VILO (Invitrogen). qRT-PCR was monitored in real time with an Mx3000 sequence detection system (Stratagene, San Diego, CA, USA) using SYBR Green (Agilent Technologies). Samples were normalized against 18 s. For Western blotting, total protein extracts were prepared from liver samples for detection of Scarb1, and Lrp. Protein extracts were electrophoresed on 4-20% gradient SDS-PAGE gels and transferred to 0.22 μm nitrocellulose membranes. The membrane was blocked in Tris-buffered saline, 0.1% Tween20 containing 5%(w/v) nonfat milk (TBST) at room temperature (RT) for 1h and then incubated with the primary antibody in TBST at RT for 4h, followed by incubation with the appropriate secondary antibody coupled to horseradish peroxidase. Proteins normalized to GAPDH were detected by ECL chemiluminescence (Pierce) and quantified by densitometry using image J software.

2.5. Statistics

Data are presented as mean± SEM. Statistical significance was performed by one-way analysis of variance (ANOVA, 4-group comparisons) with a Bonferroni multiple comparison post-test (GraphPad Prism, San Diego, CA). Statistical significance was defined by a p-value less than 0.05.

3. Results

3.1. Maintenance of euglycemia improves plasma lipoprotein levels in Ldlr−/− mice

To explore the effects of hyperglycemia on plasma lipoproteins, Ldlr−/− mice were made diabetic with STZ and fed with a high cholesterol diet (0.15%, fat free) for 4 weeks. We excluded fat from the diet to prevent any confounding effect of insulin resistance in the non-diabetic groups. We chose to feed the Ldlr−/− mice, a high cholesterol diet to promote hypercholesterolemia, a prerequisite for atherogenesis in this model. Moreover, the high cholesterol diet allowed us to determine the effect of glucose lowering (with PZ treatment) on atherosclerotic lesion progression in a condition of dyslipidemia that is often observed in diabetic subjects. Only those mice with a fasting glucose of >300mg/dl (1 mmol/l = mg/dl /18) were considered diabetic and used in the study. Induction of diabetes in Ldlr−/− mice produced severe but characteristic symptoms of T1D including hyperglycemia, hypoinsulinemia, hypertriglyceridemia, hypercholesterolemia and decreased body weight ( Fig.1 ). As expected the body weights were consistently lower ( Fig. 1A ) with higher blood glucose levels ( Fig. 1B ) and greater food intake ( Fig. 1E ) compared to non-diabetic mice. After 4 weeks of diabetes, the plasma cholesterol ( Fig. 1C ) and triglyceride levels ( Fig. 1D ) in diabetic Ldlr−/− mice were more than double compared to non-diabetic littermates. Treatment of diabetic mice with phlorizin normalized blood glucose by week 1 and maintained euglycemia for rest of the treatment period ( Fig. 1B ). Treatment with phlorizin also led to greater body weight gain in diabetic mice, even though food intake was normalized. Control of blood glucose also significantly decreased plasma total cholesterol (TC) and triglycerides (TGs) without affecting insulin levels ( Fig. 1F ). This is in contrast to WT mice with STZ diabetes that do not display significant changes in cholesterol levels [ 25].

We next examined plasma lipoprotein profiles by isolating lipoprotein participles using ultracentrifugation and analyzed the TG and cholesterol composition separately in very low density (VLDL), low density lipoproteins (LDL) and high-density lipoproteins (HDL). The total cholesterol levels in VLDL and LDL was significantly increased while TGs increased only in VLDL particles in diabetic mice compared to non-diabetic mice ( Fig. 2 ). HDL cholesterol did not change. Most importantly, treatment of phlorizin reduced cholesterol only in VLDL and LDL ( Fig. 2A ). TGs were also reduced in the VLDL particles ( Fig. 2B ). The same phenotype was observed when the mice were treated with dapagliflozin, a specific SGLT2 inhibitor, where plasma glucose, total cholesterol and triglycerides were reduced ( Supplementary Fig. 1 A- C).

3.2. Lowering glucose reduces atherosclerosis in diabetic Ldlr−/− mice

To test the hypothesis that reversal of hyperglycemia in diabetic Ldlr−/− mice would reduce atherosclerosis due to improved glycemic and lipoprotein profile, we first examined the extent of atherosclerosis in aortic arch. As shown in Fig.3 , as expected, aortic arches of diabetic mice contained significantly more atherosclerotic lesions compared to non-diabetic mice ( Fig. 3A and ). While phlorizin treatment had no effect on lesion size in the non-diabetic mice, we observed a significant reduction in lesion size in the diabetic mice ( Fig. 3A and ), consistent with similar reduction in both blood glucose and atherogenic lipoprotein levels (i.e. Figs. 1 and ). Parallel findings were observed when we quantified lesion size in the aortic root ( Fig. 3C ). We next examined the composition of the atherosclerotic lesions in the aortic root by examining lipid content using oil red O (ORO) staining and macrophage accumulation by CD68 staining. Not surprisingly, untreated diabetic mice had increased lipid and macrophage content in their lesions, while reduction in plasma lipoproteins and glucose by phlorizin led to a marked decrease in both the macrophage burden ( Fig. 3D and ) and neutral lipids ( Fig. 3F and ). These findings suggest that hyperglycemia and concurrent dyslipidemia promotes atherosclerosis while normalization of glucose using phlorizin significantly improves both the macrophage and lipid content in the lesions of diabetic mice ( Fig. 3D to ).

3.3. Lowering glucose suppresses myelopoiesis in diabetic Ldlr−/− mice

Since macrophage content in the lesions correlates positively with circulating monocytes [ 18], and monocytes are causal players in atherogenesis [ 17, 26], we next explored if changes in circulating monocytes could account for the changes observed in atherosclerosis. Previous studies have demonstrated that hyperglycemia alone [ 17] or in conjunction with dyslipidemia impacts atherosclerosis in diabetes [ 4, 16, 27]. In the setting of lesion regression with normalized lipids, this was mainly due to increased production and recruitment of inflammatory Ly6-C hi monocytes and neutrophils to the lesions [ 17]. To determine if diabetes promotes monocytosis and neutrophilia, we analyzed the blood leukocytes by flow cytometry. This revealed a significant increase in the number of circulating monocytes, particularly the Ly6-C hi cells, and neutrophils in diabetic Ldlr−/− mice compared to non-diabetic mice ( Fig. 4A and ). Further, both monocytes and neutrophils from diabetic mice were activated and primed for adhesion, as demonstrated by increased expression of CD11b in monocytes and neutrophils ( Fig. 4C ). Normalization of blood glucose with phlorizin resulted in a significant decrease in the number of monocytes, neutrophils and activation (CD11b expression) of these cells in diabetic mice without affecting the same populations in non-diabetic mice ( Fig. 4A - C ).

We next wanted to examine if increased monocytosis and neutrophilia in these mice was associated with enhanced myelopoiesis in the bone marrow and/ or spleen. Previous studies from our group and elsewhere have reported that monocytosis and neutrophilia in atherosclerosis prone Ldlr−/−, Apoe−/− or Abca1−/−/ Abcg1−/− mice fed with a cholesterol rich diet was due to enhanced proliferation of hematopoietic stem and progenitor cells (HSPCs) in the bone marrow and/ or spleen [ 17, 18, 26, 28]. To determine if diabetes promoted monocytosis and neutrophilia via increased proliferation of stem and progenitor cells, we assessed the amount of BM and spleen HSPCs that are in G2M phase of the cell cycle. Hyperglycemia in diabetic mice significantly increased the proliferation of common myeloid progenitor (CMP), granulocyte macrophage progenitor (GMP) and megakaryocyte erythroid progenitor (MEP) cells in the BM ( Fig. 4D ) but not in spleen ( data not shown). Consistent with our previous data, there was no change in the proliferation of HSPCs (LSKs) in BM ( Fig. 4D ). However, as expected lowering blood glucose led to a marked decrease in the proliferation of all myeloid progenitor cells in the BM. To understand the molecular mechanisms responsible for the myeloproliferative phenotype, we assessed the mRNA levels of Pu.1 and the CCAAT enhancer binding proteins alpha (C/ ebpα) and epsilon (C/ ebpε), the key transcriptional factors that influence the lineage commitment decision of multipotential cells. Total BM cells isolated from untreated diabetic mice showed a significant increase in Pu.1, C/ ebpα and C/ ebpε transcripts that were normalized by reversing hyperglycemia ( Fig. 4E ). These data clearly demonstrate that diabetes is associated with a myeloproliferative phenotype with increased number of highly activated circulating monocytes that could potentially contribute to increased macrophage burden and atherosclerosis.

3.4. Maintenance of euglycemia improves lipoprotein clearance via heparan sulfate proteoglycans in diabetic Ldlr−/− mice

We next asked how the reversal of hyperglycemia could possibly improve the plasma lipoprotein profile in diabetic Ldlr−/− mice. Reduced circulating LDL is likely due to either decreased synthesis of lipoproteins in the liver or improved clearance via non-LDLR pathways. Based on our previous data, we concluded that decreased lipoprotein synthesis was not driving this phenotype as we had previously found no significant difference in either apoB or TG production from the liver between control and diabetic Ldlr−/− mice [ 20]. Thus, we explored changes in other lipoprotein clearance pathways, specifically examining the Ldlr-related protein (Lrp) and Scavenger Receptor B1 (Scarb1) in the liver. mRNA expression of the liver Lrp and Scarb1 was not decreased in untreated diabetic mice ( Fig. 5A ). Surprisingly, reducing glucose in diabetic mice increased the expression of both Lrp and Scarb1. However, when we examined the protein level of these receptors by Western blotting we failed to see an increase in diabetic mice treated with phlorizin and concluded that increased lipoprotein clearance via these receptors is unlikely to have led to an improved lipoprotein profile ( Fig. 5B ).

We previously had reported that TG rich lipoproteins isolated from diabetic mice when administered to non-diabetic mice cleared much more rapidly than diabetic mice [ 20]. This defect in TG rich lipoprotein clearance was attributed by us and others to impaired heparan sulfate proteoglycans (HSPG) in the liver [ 20, 29, 30]. Therefore, we examined the role of liver HSPGs, particularly the enzymes involved in sulfation and elongation of HSPGs in the absence of Ldlr or Lrp [ 29- 31]. We specifically measured the mRNA expression of Ndst1, Ext1 and Ext2 in the liver and found a marked suppression in diabetic mice while maintenance of euglycemia by phlorizin led to a marked increase rather than mere normalization in the livers of diabetic mice ( Fig. 5C ). These data suggest that defective lipoprotein clearance in diabetic Ldlr−/− mice is likely due to hyperglycemia-mediated suppression of key enzymes involved in HSPG function.

3.5. Maintenance of euglycemia led to improved hepatobiliary excretion and cholesterol catabolism in diabetic mice

Because our data supported the hypothesis that enhanced sulfation of HSPGs with phlorizin treatment might have led to improved clearance of TG rich lipoproteins, we next sought to determine their fate in the livers. We first measured the weights of livers, which as expected showed smaller livers in the lighter STZ mice, but once normalized to body weight, revealed a significant increase in the liver to bodyweight ratio compared to control mice ( Fig. 6A ). Further, the amount of cholesterol and free fatty acids (FFAs) in the liver were higher and TGs lower in diabetic mice compared to non-diabetic mice ( Fig. 6B ). These data suggest that untreated-diabetic mice potentially had impaired lipoprotein secretion or movement into the bile from the livers, resulting in excess hydrolysis of TG to form FFAs. Phlorizin-treated diabetic mice had cholesterol levels comparable to non-diabetic mice.

The mechanism behind the phlorizin-induced decrease in plasma cholesterol levels was then explored. Dietary cholesterol has four possible fates once it reaches the liver: 1) esterification and storage in hepatocytes, 2) incorporation into VLDL particles, which are then secreted, 3) secretion directly into the bile, and 4) conversion into bile acids and secretion into the bile. The first two options were ruled out since phlorizin did not increase accumulation of cholesterol either in the liver nor did it reduce VLDL secretion. We next examined if biliary secretion of cholesterol played a role in the clearance of cholesterol from liver and thus plasma. Biliary sterol excretion is mainly executed by the two ATP-binding cassette (ABC) transporters, Abcg5 and Abcg8. The expression of Abcg5 and Abcg8 and their upstream transcription factor Lxrα, was increased when glucose levels were lowered ( Fig. 6C ). We next examined the Lxr target genes that promote cholesterol conversion to bile acids for excretion. We specifically focused on cholesterol 7 alpha-hydroxylase ( Cyp7a1), the rate-limiting enzyme in the classic bile acid biosynthetic pathway [ 32]. We found a marked increase in Cyp7a1 expression in the livers of diabetic mice, while lowering glucose suppressed its expression. Cyp27a1, an enzyme that participates in the conversion of cholesterol into bile acids, was suppressed in diabetes but increased when plasma glucose was lowered ( Fig. 6D ). Cyp2b10, another diet-inducible enzyme that plays a role in decreasing hepatic cholesterol accumulation via formation of polyhydoxylated bile acids was dramatically upregulated in diabetes and further increased in phlorizin-treated diabetic mice. These data suggest that lowering blood glucose promotes lipoprotein clearance via mechanisms that involve increased secretion and catabolism of cholesterol into bile acid pathways.

4. Discussion

It is well know that deposition of cholesterol-rich lipoproteins in the arterial wall initiates atherosclerosis but that the entry of inflammatory monocytes propagates the disease [ 33]. Accordingly, the potential for monocyte recruitment into the lesion is strongly affected by the number and phenotype of circulating monocytes [ 26], implying that monocyte availability in the circulation may be one of the rate-limiting step for atherogenesis [ 18]. We recently reported that in mouse models of T1D, hyperglycemia alone impairs atherosclerotic lesion regression by increasing the number of inflammatory Ly6-C hi monocytes in the blood and their entry into the lesions [ 17]. These findings led us to hypothesize that a tighter glycemic control in diabetes, which is often associated with improvements in plasma lipids [ 2], would reduce atherosclerosis, accompanied by reductions in monocytes and neutrophils. Indeed, we found treating diabetic mice with sodium glucose cotransporter inhibitors, a class of clean glucose lowering agents improved lipid profiles, reduced the size of atherosclerotic lesions, and reduced the number of myeloid cells in the blood.

Both hyperglycemia and hyperlipidemia can independently promote leukocytosis and accelerate atherosclerosis [ 17, 18, 26]. For that reason, we sought to separate these two factors to determine which was the more potent effector of circulating monocyte levels. Our previous studies had shown that hypercholesterolemia stimulated HSPCs proliferation in the BM [ 26], while hyperglycemia affected CMPs and GMPs that are at a later stage of differentiation [ 17]. Treatment of diabetic mice reduced levels of glucose and cholesterol in Ldlr−/− mice, but their effects on the BM were confined to reductions in CMPs and GMPs. Thus, although this is a model of hyperglycemia and hypercholesterolemia, the benefits of phlorizin on reducing myelopoiesis appeared to be due to the glucose lowering via reduction in the more committed progenitors [ 34]. However, as lipids do regulate the proliferation of these progenitors, we cannot definitively rule out the contribution of lipids. Nonetheless, SGLT inhibition has a net positive effect on BM myelopoiesis.

Lipoprotein metabolism is complex and highly regulated, such that multiple pathways contribute to the total pool of plasma cholesterol. Our data suggested a defect in the HSPG-regulated lipoprotein clearance pathway. Clearance of lipoproteins by HSPGs is rapid and involves their trapping and internalization by endocytosis within the liver's perisinusoidal space (space of Disse) through electrostatic binding. We previously had reported the suppression of Ndst1, a key biosynthetic enzyme that regulates the overall level of sulfation of HSPGs, led to defective lipoprotein clearance in diabetic mice [ 20, 35, 36]. HSPGs are decorated with heparan sulfate chains on a proteoglycan backbone and the assembly of these chains including their initiation and elongation is catalyzed by members of the exostosin family (Ext) [ 37, 38]. Given the importance of HSPGs in regulating lipoprotein clearance, restoration of Ndst1, Ext1 and Ext2 expression levels by normalizing blood glucose using phlorizin is consistent with our previous observations of defective lipoprotein clearance in diabetes.

Since normalization of hyperglycemia led to a significant decrease in plasma lipoproteins presumably by an efficient clearance mechanism mediated by HSPGs, we next examined the fate of lipoproteins, particularly the cholesterol in the liver. Cholesterol homeostasis is controlled by a series of regulatory pathways via synthesis of endogenous cholesterol, absorption from the diet and elimination by secretion or conversion to bile acids. A previous study by our group found no differences either in the synthesis or dietary absorption of cholesterol in Ldlr−/− diabetic mice [ 20]. Other processes such as biliary secretion and/ or conversion to bile acids may play a vital role in the clearance of lipoproteins. Biliary excretion of cholesterol is mainly regulated by Abcg5 and Abcg8, the two "half transporters" that are predominantly expressed in hepatocytes and under the transcriptional control of liver X receptor (Lxrα) [ 39]. Polymorphisms in either of these genes have led to elevated phytosterols in the plasma and premature atherosclerosis [ 40] mainly due to enhanced intestinal absorption and decreased biliary excretion of sterols [ 41]. Accordingly, mice deficient in Abcg5/ Abcg8 genes have reduced ability to secrete sterols into bile while overexpression of Abcg5/ Abcg8 in the liver reduces diet-induced increase in hepatic cholesterol content [ 42] by facilitating biliary secretion and suppressing intestinal cholesterol absorption [ 43]. We found that normalization of glucose by phlorizin led to a significant increase in the expression of both Abcg5 and Abcg8 as well as their transcriptional regulator Lxrα. These data suggest that some of the dietary cholesterol that was absorbed into the liver was channeled towards the bile. Whether this is mediated directly by hyperglycemia is unclear, but it is interesting to note that phlorizin treatment in control mice did not lead to overexpression of Abcg5, Abcg8 or Lxrα. Thus, it is unlikely that phlorizin has off target effects that directly induces the expression of these genes.

We next assessed the Lxr target genes that promotes excretion of cholesterol in the form of bile acids. We specifically focused on Cyp7a1, Cyp27a1, and Cyp2b10. Previous studies have demonstrated increased expression of Cyp7a1 along with increased bile acid pool and fecal bile acids in STZ diabetic mice. In line with this, we also found a significant increase in Cyp7a1 expression in the livers of untreated diabetic mice that might have led to enhanced fecal excretion of cholic and deoxycholic acids. These bile acids have lower critical micelle concentration [ 44] and therefore efficiently reabsorbed into the circulation and ultimately to the liver [ 45]. Similarly, Cyp27a1, an enzyme that plays an important role in cholesterol catabolism to bile acids was suppressed in diabetic livers [ 46] and reversed when blood glucose was lowered. Cyp2b10, another diet-inducible enzyme that decreases hepatic cholesterol accumulation via formation of polyhydoxylated bile acids was upregulated in phlorizin-treated diabetic mice. These data suggest that lowering blood glucose promotes hepatic cholesterol degradation leading to enhanced bile acid formation and their effective removal by suppressing entero-hepatic recycling. However, further studies are required to examine the precise molecular mechanisms that led to efficient clearance of hepatic cholesterol via bile acid pathways.

In summary, we have studied the effect of reversal of hyperglycemia on accelerated atherosclerosis using a mouse model of STZ-induced diabetes in Ldlr−/− background fed with high cholesterol diet. Our model mimics an hyperlipidemic condition that is often found in T1D humans in Western society with poorly controlled blood glucose levels, high fat diet and reduced Ldlr activity due to insulin deficiency [ 47]. In concert with our previous observations, we found that poorly controlled hyperglycemia led to defective lipoprotein clearance [ 20] and hepatobiliary excretion of cholesterol. This was associated with increased number of circulating monocytes and their precursor cells in the BM as well as increased lipid and macrophage content in atherosclerotic lesions. In this situation, the hyperglycemic effects on the BM were more pronounced than the effect of hyperlipidemia. Reversal of hyperglycemia not only led to improvement in plasma and liver lipoprotein profiles but also significantly reduced atherosclerosis. These data underscore the importance of tighter blood glucose control to prevent acute coronary syndromes particularly in T1D subjects who are at greater risk of developing atherosclerosis.

​

SGLT2 inhibitors reduce hyperglycemia, monocytosis and atherosclerosis development

Reversal of hyperglycemia improves plasma lipid profile

Improved lipoprotein profile is achieved mainly by hepatic HSPG and bile acid pathways

SGLT2 inhibitors can be used as a lipid lowering drug in diabetics with dyslipidemia

Supplementary Material

1

Fig. S1. SGLT2 specific inhibitor (dapagliflozin) reduces blood glucose, total cholesterol and triglycerides.

Diabetic and non-diabetic Ldlr−/− mice on cholesterol-rich diet (0.15%) were treated with either vehicle or dapagliflozin (25 mg/kg b.w in drinking water) for 4 weeks. Plasma was collected from 6 hour-fasted mice and analyzed for glucose, total cholesterol and TG as described in methods. (A) Total blood glucose levels with SGLT2 inhibitor treatment. (B) Total plasma cholesterol and (C) plasma triglyceride levels.

Acknowledgements

We acknowledge the assistance from the Flow Cytometry and Imaging Core Facilities at Columbia University and UAB. We thank Dr. Ashish Dhyani for his assistance in manuscript preparation.

Financial support

PRN is supported by grants from the NIH (HL122505, HL137799) and IJG (DK095684). A.J.M is supported by a NHMRC grant (APP1106154), a Career Development Fellowship from the NHMRC (APP1085752) and a Future Leader Fellowship from the National Heart Foundation (100440).

Footnotes

Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Conflict of Interest

The authors declared they do not have anything to disclose regarding conflict of interest with respect to this manuscript.

References

3. Renard CB, et al., Diabetes and diabetes-associated lipid abnormalities have distinct effects on initiation and progression of atherosclerotic lesions. J Clin Invest, 2004. 114: p. 659-68. [[ PubMed] PMC free article] [ Google Scholar]

5. Dandona P, et al., Insulin as an anti-inflammatory and antiatherosclerotic hormone. Clin Cornerstone, 2003. Suppl 4: p. S13-20. [[ PubMed] Google Scholar]

9. Du X, et al., Insulin resistance reduces arterial prostacyclin synthase and eNOS activities by increasing endothelial fatty acid oxidation. J Clin Invest, 2006. [[ PubMed] PMC free article] [ Google Scholar]

16. Parathath S, et al., Diabetes Mellitus Adversely Affects Macrophages During Atherosclerotic Plaque Regression in Mice. Diabetes, 2011. [[ PubMed] PMC free article] [ Google Scholar]

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SGLT2 inhibition reduces atherosclerosis by enhancing lipoprotein clearance in Ldlr−/− type 1 diabetic mice

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Atherosclerosis. Author manuscript; available in PMC 2020 May 3. Published in final edited form as: Annas Al-Sharea, 2, ^ Andrew J. Murphy, 1, 2, ^ Huggins LA, 1, 3 Hu Y, 1, 3 Ira J. Goldberg, 1, 3 and Prabhakara R Nagareddy 1, 4, * Leukocytosis, particularly monocytosis, has been shown to promote atherosclerosis in both diabetic and non-diabetic mouse models.

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Impact of multi-micronutrient supplementation on lipidemia of children and adolescents - Dierra Doaks 

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Impact of multi-micronutrient supplementation on lipidemia of children and adolescents - Dierra Doaks 

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This research article focuses on the effects of multi-nutrients on Brazilian children and teens with lipoprotein alterations and lipid metabolism. This is an important article because micronutrient supplementation has been explored heavily to reduce chronic diseases. The main purpose of the study was to determine how supplementation effects circulating lipids. Vitamin E and vitamin A are fat soluble and have antioxidant characteristics. They also interact with lipoproteins which can impact lipid metabolism and lipidemia. The study involved children between the ages of 9 and 13 years old. They were given nutrients including vitamin A, Vitamin E, folate, Vitamin B, Iron, Calcium, phosphate, and more. Lipid extraction and other analyses were performed on each child. The results of the study suggested that there may be an impact on macronutrients on lipidemia, total triglyceride, and cholesterol levels. This relates to the class because we are actively learning how our diet affects dyslipidemia.

Chakrabarti, Anirikh et al. “Impact of Multi-Micronutrient Supplementation on Lipidemia of Children and Adolescents.” Clinical nutrition (Edinburgh, Scotland) 39.7 (2020): 2211–2219. Web.

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Cholesterol-Lowering Effects of Extract from Garcinia daedalanthera in Hyperlipidemic Rats -Clarisa Williams

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Cholesterol-Lowering Effects of Extract from Garcinia daedalanthera in Hyperlipidemic Rats -Clarisa Williams

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Najib, S. Z., Fachri, W., Sauriasari, R., Elya, B., & Tjandrawinata, R. (2018). Cholesterol-lowering Effects of Extract from Garcinia daedalanthera in Hyperlipidemic rats. Pharmacognosy Journal, 10(6).

This study investigates the effects of an Indonesian native plant, Garcinia daedalanthera, and its potential impacts on lipid profiles in hyperlipidemic rats.  Utilizing natural medicines have always maintained interest as an alternative method for treatment. The therapeutic properties of Garcinia daedalanthera are believed to include antihyperlipidemic activity.  A dietary supplementation of  Garcinia daedalanthera extract were given in doses. Serum lipid levels were collected on the start of date of the high fat diet, in the middle of the experimental duration, and last at the end of the intervention. Dietary supplementation of Garcinia daedalanthera extract reduced serum LDL levels in high fat diets. The decrease in LDL levels occurred with doses of 10mg per kg of body weight and 100mg per kg of body weight in hyperlipidemic rats. This study relates to nutritional sciences as the intervention of this natural medicine can impact overall health in individuals with high lipid profiles and potentially dyslipidemia. The clinical implications of this study would be to utilize a concentrate of the Garcinia daedalanthera leaves to reduce the serum LDL levels of patients with high fat diets or higher LDL cholesterol levels. Garcinia daedalanthera is a promising supplement that would be a beneficial addition to a nutritional intervention.

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Kate Mashburn - A low-carbohydrate, ketogenic diet versus a low-fat diet to treat obesity and hyperlipidemia: a randomized, controlled trial

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Kate Mashburn - A low-carbohydrate, ketogenic diet versus a low-fat diet to treat obesity and hyperlipidemia: a randomized, controlled trial

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This study aimed to compare the results of a low carbohydrate diet with the results of a ketogenic diet, low fat diet, and low-calorie diet. The participants of the study were overweight and hyperlipidemic volunteers. The measurements consisted of body weight and composition along with tolerability of the participants. The results were very similar in the low carbohydrate diets and the low-fat diets. However, there were more negative side effects observed from the low carbohydrate diet group. Serum triglyceride levels decreased more while high-density lipoprotein cholesterol levels increased more for the volunteers participating in the low carbohydrate diet. I find it very interesting that the majority of the studies I find every week that aim to reduce the side effects of disease often focus on weight loss. It just strengthens my understanding that living a healthier lifestyle can greatly decrease a persons chances of developing a disease while also reducing the side effects if one is ultimately developed.

https://pubmed.ncbi.nlm.nih.gov/15148063/

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Affiliation

¹ Center for Health Services Research in Primary Care, Department of Veterans Affairs Medical Center, and Duke University Medical Center, Durham, North Carolina 27705, USA.

Free article

Free article

Affiliation

¹ Center for Health Services Research in Primary Care, Department of Veterans Affairs Medical Center, and Duke University Medical Center, Durham, North Carolina 27705, USA.

Abstract

Background: Low-carbohydrate diets remain popular despite a paucity of scientific evidence on their effectiveness.

Objective: To compare the effects of a low-carbohydrate, ketogenic diet program with those of a low-fat, low-cholesterol, reduced-calorie diet.

Design: Randomized, controlled trial.

Setting: Outpatient research clinic.

Participants: 120 overweight, hyperlipidemic volunteers from the community.

Intervention: Low-carbohydrate diet (initially, <20 g of carbohydrate daily) plus nutritional supplementation, exercise recommendation, and group meetings, or low-fat diet (<30% energy from fat, <300 mg of cholesterol daily, and deficit of 500 to 1000 kcal/d) plus exercise recommendation and group meetings.

Measurements: Body weight, body composition, fasting serum lipid levels, and tolerability.

Results: A greater proportion of the low-carbohydrate diet group than the low-fat diet group completed the study (76% vs. 57%; P = 0.02). At 24 weeks, weight loss was greater in the low-carbohydrate diet group than in the low-fat diet group (mean change, -12.9% vs. -6.7%; P < 0.001). Patients in both groups lost substantially more fat mass (change, -9.4 kg with the low-carbohydrate diet vs. -4.8 kg with the low-fat diet) than fat-free mass (change, -3.3 kg vs. -2.4 kg, respectively). Compared with recipients of the low-fat diet, recipients of the low-carbohydrate diet had greater decreases in serum triglyceride levels (change, -0.84 mmol/L vs. -0.31 mmol/L [-74.2 mg/dL vs. -27.9 mg/dL]; P = 0.004) and greater increases in high-density lipoprotein cholesterol levels (0.14 mmol/L vs. -0.04 mmol/L [5.5 mg/dL vs. -1.6 mg/dL]; P < 0.001). Changes in low-density lipoprotein cholesterol level did not differ statistically (0.04 mmol/L [1.6 mg/dL] with the low-carbohydrate diet and -0.19 mmol/L [-7.4 mg/dL] with the low-fat diet; P = 0.2). Minor adverse effects were more frequent in the low-carbohydrate diet group.

Limitations: We could not definitively distinguish effects of the low-carbohydrate diet and those of the nutritional supplements provided only to that group. In addition, participants were healthy and were followed for only 24 weeks. These factors limit the generalizability of the study results.

Conclusions: Compared with a low-fat diet, a low-carbohydrate diet program had better participant retention and greater weight loss. During active weight loss, serum triglyceride levels decreased more and high-density lipoprotein cholesterol level increased more with the low-carbohydrate diet than with the low-fat diet.

Adherence to Low-Carbohydrate Diets in Patients with Diabetes: A Narrative Review.

Kumar NK, Merrill JD, Carlson S, German J, Yancy WS Jr. Kumar NK, et al. Diabetes Metab Syndr Obes. 2022 Feb 18;15:477-498. doi: 10.2147/DMSO.S292742. eCollection 2022. Diabetes Metab Syndr Obes. 2022. PMID: 35210797 Free PMC article. Review.

Low-carbohydrate versus balanced-carbohydrate diets for reducing weight and cardiovascular risk.

Naude CE, Brand A, Schoonees A, Nguyen KA, Chaplin M, Volmink J. Naude CE, et al. Cochrane Database Syst Rev. 2022 Jan 28;1(1):CD013334. doi: 10.1002/14651858.CD013334.pub2. Cochrane Database Syst Rev. 2022. PMID: 35088407 Free PMC article. Review.

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dietary carbohydrates / administration & dosage*

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national center for biotechnology information

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A low-carbohydrate, ketogenic diet versus a low-fat diet to treat obesity and hyperlipidemia: a randomized, controlled trial - PubMed

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Compared with a low-fat diet, a low-carbohydrate diet program had better participant retention and greater weight loss. During active weight loss, serum triglyceride levels decreased more and high-density lipoprotein cholesterol level increased more with the low-carbohydrate diet than with the low-f ...

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Sidney Harm: The effect of olive leaf extract on cardiovascular health markers: a randomized placebo-controlled clinical trial

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Sidney Harm: The effect of olive leaf extract on cardiovascular health markers: a randomized placebo-controlled clinical trial

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This study investigated the effects of olive leaf extract supplementation on cardiovascular disease biomarkers such as lipid levels and blood pressure. This is related to nutritional sciences due to the fact the possible impact the extract could have on individuals overall health; high blood pressure and high cholesterol prevalence is increasing within the US. This is an important topic to research and investigate what ways individuals can naturally decrease these biomarkers and their risk for developing cardiovascular disease. The sample population of this study included 74 individuals that were overweight or obese with mild elevated biomarkers, divided between two groups; a treatment group who received 500 mg of the extract or the control who received a placebo. The lab parameters were measured in each individual by 4 weeks of treatment and then again at 8 weeks. Unfortunately, there was so significant difference found between the groups at either time in any of the parameters being investigated. These results could have been impacted based on the amount the treatment group received.

References:
Stevens, Winkens, B., Jonkers, D., & Masclee, A. (2020). The effect of olive leaf extract on cardiovascular health markers: a randomized placebo-controlled clinical trial. European Journal of Nutrition, 60(4), 2111–2120. https://doi.org/10.1007/s00394-020-02397-9

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Breast Cancer Patients and the Effects of Chemotherapy on their Plasma Lipids and Lipid Metabolism- Lydia Duncan

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Breast Cancer Patients and the Effects of Chemotherapy on their Plasma Lipids and Lipid Metabolism- Lydia Duncan

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This study evaluated if agents of chemotherapy can alter plasma lipids and lipid metabolism, specifically in breast cancer patients. This was done by taking the blood samples of 12 women at the beginning, midpoint, and end of the treatment to compare the lipid levels. This study is important for multiple reasons. First, it is always beneficial to at least have an idea of how a patient's body will react to certain treatment, backed by credible research. Of course, each person reacts to treatments in an individualized way, but studies like this help show the side effects from treatment of one disease can have an affect on another portion of an individual's health (by comparing multiple individual's levels). Second, it is important because if there is link between chemotherapy and lipid metabolism, systems must be put in place to make sure those effects are reduced or monitored.

One key finding from this study was that Chemotherapy does alter HDL'S, LDL's, and other associated apolipoprotein levels in breast cancer patients. For HDL's, over the full time of the treatment, the mean level started at 1.45mmol/L and ended at 1.13mmol/L. Therefore, there was an overall decrease in the amount of HDL's. Because of the decrease in HDL's, there was also a reduction in apolipoprotein A1 levels. The baseline level at the start of the experiment was 1.81g/L, and the mean levels at the end of the treatment were 1.61g/L. For LDL's, chemotherapy treatment showed an increase in said LDL particles. The average at the start of the study was 3.11mmol/L, and the average at the end of the study was 3.69mmol/L. The increase in LDL particles also led to an increase in apolipoprotein B levels. The baseline started at 0.97g/L, and by the end of the treatment the average levels were 1.12g/L. These result relate to nutritional science because we have seen how low levels of HDL and high levels of LDL are risk factors for diseases like cardiovascular disease. Continuing off of that, an interesting way this study could be continued is by examining the number of individuals who develop CVD after undergoing chemotherapy for breast cancer. One overall limitation of this study is that a larger cohort is needed to fully understand how lipid metabolism can affect large groups of different people.

A clinical application from this study is that the chemotherapy agents used in treatment are important. Most of the lipid side effects came from Doxorubicin and Paclitaxil. On the other hand, Cyclophosphamide seemed to have no effect on lipid metabolism. Another application is that lipid levels should be monitored in individuals undergoing chemotherapy for breast cancer. That way, dietary or supplemental arrangements could be made to keep up HDL levels and decrease LDL levels while undergoing chemotherapy treatment for breast cancer.

Sharma, M., Tuaine, J., McLaren, B., Waters, D. L., Black, K., Jones, L. M., & McCormick, S. P. (2016). Chemotherapy agents alter plasma lipids in breast cancer patients and show differential effects on lipid metabolism genes in liver cells. PLOS ONE, 11(1). https://doi.org/10.1371/journal.pone.0148049

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Chemotherapy Agents Alter Plasma Lipids in Breast Cancer Patients and Show Differential Effects on Lipid Metabolism Genes in Liver Cells

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Cardiovascular complications have emerged as a major concern for cancer patients. Many chemotherapy agents are cardiotoxic and some appear to also alter lipid profiles, although the mechanism for this is unknown. We studied plasma lipid levels in 12 breast cancer patients throughout their chemothera…

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Low fat diets, lipoprotein subclasses, and heart disease risk. -Jaida Garrett 

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Low fat diets, lipoprotein subclasses, and heart disease risk. -Jaida Garrett 

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This article compares and contrast previous studies done regarding diets given to patients to lower LDL levels who may be at risk for coronary heart disease. A key finding was that the best prediction of a low total fat intake diet would be for individuals with already elevated LDL levels or dense LDL particles. This diet shouldn’t be recommended to everyone especially for those who have lipoprotein profiles indicating a low risk for coronary heart disease due to adverse metabolic changes that come with diets. What is important before switching the diet completely is assessing metabolic response to diets in total and saturated fats in order to see what can or cannot be substituted. This information is helpful for nutritionist and physicians because it will help each patient differently. For example, I was under the impression that in order to lower risk for heart disease replacing bad fat with good fat is beneficial for everyone and while that may be beneficial at first it can hurt someone in the long run. So, understanding what a patient may be at risk for and their overall nutrient composition will help treat different individuals of different backgrounds.

Low fat diets, lipoprotein subclasses, and heart disease risk. Academic.oup.com. (n.d.). Retrieved March 29, 2022, from https://academic.oup.com/

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Dietary patterns based on carbohydrate nutrition are associated with diabetes and dyslipidemia

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Dietary patterns based on carbohydrate nutrition are associated with diabetes and dyslipidemia

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Ellen Reusch

For this week's wall, I found this 2005 article focusing on dietary patterns and carbohydrate intake in Asian populations. Nearly 10,000 subjects (3,795 men and 5,930 women) were interviewed and asked questions regarding their diet using a 24-hour recall system. Two groups were identified within the subject population by analyzing their quantity and quality of carbohydrate intake. One group included those who had a balanced pattern of carbohydrate intake, which did include white rice. The second group exhibited a rice-oriented eating pattern, characterized by high rice intake but low intake of vegetables, fruits, and meats. The researchers then analyzed each group's prevalence of diabetes and dyslipidemia. The balanced pattern did not show any increased prevalence of either metabolic condition, but the subject group with carbohydrate-focused nutrition did show increased incidence of diabetes and dyslipidemia in the subject population interviewed for this study.

I think this article is important because it solidified the basis of the most basic dietetic advice - to eat a balanced diet with fruits, vegetables, meats, AND carbohydrates. It could be used as additional evidence for physicians or care providers when they need to convince their patients to maintain these healthy diet patterns even prior to the development of any nutritionally-fueled disease or condition. I think it would be interesting to expand this study to a wider range of subjects throughout the world, not just in the Korean or Asian populations. This limited background could potentially lead to some other influences outside of just nutritional carbohydrate intake, and the presence of other independent variables could potentially be confirmed with the completion of other studies throughout other world populations.

Reference: Song, Su Jin, et. al., Dietary patterns based on carbohydrate nutrition are associated with diabetes and dyslipidemia. Nutrition Research and Practice. 2005. https://synapse.koreamed.org/articles/1051237

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Dietary pattern analysis has drawn considerable attention in studies to examine the relationships between diet and disease, as it measures the effect of the overall diet beyond that of single foods or nutrients. Among large-scaled prospective studies, Hu et al. [ 1] identified a Western vs. a prudent pattern in the U.S. population and reported that the Western pattern was associated with increased risks and that the prudent pattern was associated with decreased risks for cardiovascular disease [ 1, 2] and diabetes [ 3]. Along with that study, several other Western studies [ 4- 7] have focused on Western and prudent/healthy dietary patterns associated with risk factors for diabetes, cardiovascular disease, and metabolic syndrome.

However, Asian countries have a different dietary culture, although the Western pattern has emerged in the Asian population, yet it differs from that of the Western population because staple foods such as rice are still major sources in the diet. With rapid economic growth, Western patterns among Asian populations, characterized by increased consumption of animal food including meat, bread, and butter as well as sweet desserts, have shown inconsistent relationships with metabolic risk factors, although it is difficult to compare studies due to different dietary pattern analysis methodologies. A Western pattern was associated with higher total, high density lipoprotein (HDL)-, and low density lipoprotein (LDL)-cholesterol in the Japanese population [ 8] and a meat-rich pattern was associated with an increased risk for diabetes in the Chinese population [ 9]. A meat and alcohol pattern was associated with elevated fasting glucose and serum triglycerides in the Korean population [ 10]. In contrast, a westernized breakfast pattern was associated with a reduced risk for elevated glycated hemoglobin concentrations (≥ 5.5%) in the Japanese population [ 11] and a Western pattern was associated with reduced risks for elevated fasting glucose and low HDL-cholesterol in Korean women [ 12].

Among these inconsistent findings, the quantity and quality of carbohydrate intake contributes to metabolic abnormalities, as the Asian diet is typically a high carbohydrate diet, which can raise fasting glucose and triglycerides but reduce HDL-cholesterol. Among several studies on dietary carbohydrates, the glycemic index (GI) was reportedly associated with metabolic risk factors in Asian populations [ 13- 15], but no study has been conducted on dietary patterns based on carbohydrate nutrition.

A recently proposed method of dietary pattern analysis is reduced rank regression (RRR), which uses intermediary information that best explains the variance in a set of response variables selected with prior knowledge [ 16, 17]. The RRR identifies dietary patterns that explain a combined set of known risk factors and the findings on the association between dietary patterns identified and chronic disease risk provides important information for a disease prevention strategy. Hoffmann et al. [ 18] derived dietary patterns using percentages of energy from saturated fat, polyunsaturated fat, protein, and carbohydrate as response variables, and those patterns were associated with all-cause mortality. McNaughton et al. [ 19] identified a dietary pattern using fasting glucose and fasting insulin as response variables and that pattern was associated with type 2 diabetes.

Thus, we applied RRR to identify specific dietary patterns in an Asian population. The aim of this study was to identify dietary patterns that explain the maximal variation in carbohydrate quantity and quality and to examine the relationship between dietary patterns and metabolic risks for dyslipidemia and diabetes among the Korean adult population.

In this study, two dietary patterns, termed balanced and rice-oriented, were identified using RRR. The rice-oriented pattern was significantly associated with an increased prevalence of dyslipidemia in both men and women. In men, the balanced pattern was associated with reduced prevalence of diabetes when energy intake was above the median, whereas the rice-oriented pattern was associated with increased prevalence of diabetes when energy intake was below the median.

Different from previous studies of dietary patterns for Asian populations, we derived dietary patterns focusing on carbohydrate nutrition. White rice was a major contributor in both patterns, although with different carbohydrate quantity and quality, reflecting the Asian diet quite well.

Our most interesting finding was that men in the highest quintile of the rice-oriented pattern, characterized by high white rice intake and low intake of other foods, had a 58% increased prevalence of hypertriglyceridemia and a 43% increased prevalence of low HDL-cholesterol compared to those in the lowest quintile, whereas the balanced pattern, characterized by high intake of various kinds of foods, was not associated with dyslipidemia. Women with a higher score for the rice-oriented pattern were also positively associated with low HDL-cholesterol.

White rice is associated with an increased risk for diabetes in Japanese [ 28] and U.S. individuals [ 29], and ischemic stroke in the Chinese [ 30]. Given that white rice was the highest loading in both patterns, meal composition would be more influential than white rice intake itself. In the Korean diet, rice, soup, and side dishes are a typical meal, and the type of food in these side dishes would be a core factor for diet variation. The balanced pattern included vegetables, fruits, and dairy products, which beneficial for health, whereas the rice-oriented pattern had low consumption of these foods. Several prospective studies [ 31- 33] have suggested that intake of vegetables, fruits, and dairy products are inversely related to risks for metabolic abnormalities such as diabetes, dyslipidemia, and metabolic syndrome.

In our study, the two dietary patterns differed in carbohydrate quantity and quality. Subjects in the highest quintile of the rice-oriented pattern showed lower energy and total carbohydrate intake but higher GI and percentage of energy from carbohydrate than those in the highest quintile of the balanced pattern.

High carbohydrate intake or a high GI diet has adverse effects on serum lipid levels and glucose metabolism [ 13, 15, 34- 36], which are likely due to increase risks for metabolic abnormalities such as diabetes [ 37, 38] and cardiovascular disease [ 39]. Although many studies have reported a positive association between GI and diabetes, two large cohort studies [ 40, 41] did not find any association between GI and diabetes incidence. Considering that GI alone cannot fully explain the effects of diet on metabolic abnormalities, dietary pattern, which captures the overall quality of the diet, would be more important than solely a high carbohydrate diet or a high GI diet.

We also found that the balanced pattern was associated with reduced prevalence of diabetes under high energy intake, whereas the rice-oriented pattern was associated with an increased prevalence of diabetes under low energy intake in men. We have no clear answer for the favorable effects of the balanced pattern when energy intake was only above the median. The protective effect of the balanced pattern on diabetes may represent the beneficial effects of a variety of nourishing foods and a low GI diet on glucose metabolism. A possible explanation is that if energy intake is low, it represents that overall nutrition status is poor. According to Choi and Kim [ 42], total energy and intake of particular micronutrients were significantly lower among diabetic patients than non-diabetics in the Korean population. Another study [ 43] showed significantly low intakes of energy, carbohydrate, potassium, riboflavin, niacin, and dietary fiber among hyperinsulinemic individuals. Slabber et al. [ 44] concluded that optimal nutrition might play an important role in the prevention of diabetes mellitus. This supports the notion that the balanced pattern would be effective to reduce risk of diabetes if proper energy intake is provided.

This study had several limitations. First, the cross-sectional design made it difficult to examine the causal relationships between dietary patterns and metabolic abnormalities. Rather, this study represents more of a hypothesis-generating approach. Second, we used dietary data from a single 24-hour recall, which might not represent usual intake. Third, the GI calculation was based on international tables in which most foods were derived from Western countries. The development or validation of GI values for Korean foods is necessary in the near future.

Regardless of these limitations, to our knowledge, this is the first study to derive dietary patterns using the RRR method based on carbohydrate-related dietary factors in an Asian population. Factor analysis derives dietary patterns by maximizing the explained variation of all predictor variables, whereas RRR provides linear functions of predictor variables that explain as much of the variation in response variables (e.g., biomarkers or nutrients) as possible [ 16]. The RRR method has an advantage to combine dietary information with prior knowledge about the pathway from diet to disease. Thus, the RRR method may be a useful tool for identifying dietary patterns related to the risk for diabetes or dyslipidemia. This study also included a relatively large representative sample of the Korean population, so it captured an entire spectrum of carbohydrate intake and serum indicators. Additionally, we excluded subjects who had been previously diagnosed or treated for diabetes, dyslipidemia, or hypertension, so that our results would be meaningful to provide proper nutrition information for healthy adults to prevent chronic disease.

In conclusion, we derived two dietary patterns based on carbohydrate quantity and quality among the Korean adult population. The rice-oriented pattern was associated with increased risk for dyslipidemia whereas the balanced pattern was associated with reduced risk for diabetes when energy intake was adequate. Our findings imply that dietary patterns based on carbohydrate nutrition should be considered together with other foods consumed rather than considering the sole effect of a single food item such as white rice. Further prospective or intervention studies are necessary to confirm our findings.

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Dietary pattern analysis has drawn considerable attention in studies to examine the relationships between diet and disease, as it measures the effect of the overall diet beyond that of single foods or nutrients. Among large-scaled prospective studies, Hu et al. [ 1] identified a Western vs. a prudent pattern in the U.S.

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Tamunoerenomie Inimgba: Green tea leaf powder prevents dyslipidemia by modulating gut microbiota

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Tamunoerenomie Inimgba: Green tea leaf powder prevents dyslipidemia by modulating gut microbiota

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The purpose of the study is to examine the effects of green tea leaf powder in reducing hyperlipidemia effects and to understand the effects it has on different forms of lipid metabolism. Green tealeaf powder is known to be reach in dietary fiber and previous studies have shown that it has various beneficial effects on human health. The study however aims to study the prebiotic role of tea leaf powder and its effect on gut microbiota. The study was carried out in mice and a key result was the green leaf tea powder improves lipid metabolism of high-fat diet fed mice in a dose dependent manner, which would help in reprogramming gut microbiota, and decreasing systemic inflammation. This shows that the green tea leaf powder had a preventive effect on dyslipidemia. This relates to nutritional sciences as diet and gut microbiota play important roles in regulation of dyslipidemia and help regulate underlying mechanisms which would result in an improvement of the disease due to reduction or increase in consumption of certain foods. The clinical implications of this article would be to identify and verify more foods that help in lowering LDL levels and increasing HDL levels in order to provide patients with better health outcomes and reduce health risks due to cardiovascular disease and high cholesterol levels.

Wang, Li, P. P., Liu, S. S., Zhang, B. B., Hu, Y. Y., Ma, H. H., & Wang, S. S. (2020). Green tea leaf powder prevents dyslipidemia in high-fat diet-fed mice by modulating gut microbiota. Food & Nutrition Research, 64, 1–14. https://doi.org/10.29219/fnr.v64.367

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Rhoda Inimgba: Frequency and Quantity of Egg Intake Is NotAssociated with Dyslipidemia: The Hellenic NationalNutrition and Health Survey (HNNHS).

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Rhoda Inimgba: Frequency and Quantity of Egg Intake Is NotAssociated with Dyslipidemia: The Hellenic NationalNutrition and Health Survey (HNNHS).

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The paper is important because cardiovascular disease is one of the leading cause of death in the world. One important change thatcan be made to reduce the mortality rate of cardiovascular disease is diet and lifestyle change. This paper focuses on the relationship between the amount of egg consumption and dyslipidemia which thereby leads to cardiovascular disease. This is because eggs are nutrient dense foods which are low in saturated fats but are a very good source of cholesterol. This is a major reason why it is important to see if egg consumption can bring about an increase in cardiovascular disease.
One key finding of the study was that there was a significant lower levels of serum cholesterol and LDL-c in both models when patients consumed a lot of eggs and rarely consumed eggs. This relates to nutritional sciences as it provides information about food that can provide individuals with dyslipidemia cholesterol without increasing their mortality rate. The clinical implications of this study is that it gives physicians an extra food option to recommend to their patients that suffer from cardiovascular disease without putting them at risk of getting more ill.

Magriplis, Mitsopoulou, A.-V., Karageorgou, D., Bakogianni, I., Dimakopoulos, I., Micha, R., Michas, G., Chourdakis, M., Chrousos, G. P., Roma, E., Panagiotakos, D., & Zampelas, A. (2019). Frequency and Quantity of Egg Intake Is Not Associated with Dyslipidemia: The Hellenic National Nutrition and Health Survey (HNNHS). Nutrients, 11(5), 1105–. https://doi.org/10.3390/nu11051105.

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The article I chose this week examines combined dyslipidemia, a lipid abnormality in childhood. Combined dyslipidemia is characterized as moderate to severe elevation in triglycerides and non high density lipoprotein cholesterol, minimally elevated LDL-C, and reduced HDL-C. Combined dyslipidemia is primarily associated with obesity in childhood and is also a good predictor of atherosclerosis and early clinical cardiovascular events in adulthood. The study examined the role of weight loss, increased physical activity, and diet change on lipid composition. The combination of lifestyle changes is the primary form of treatment for CD. According to the article, small amounts of weight loss are associated with a decrease in triglyceride levels and an increase in HDL-C levels. However, once children become less active, their triglyceride levels return to baseline. Children who followed a carbohydrate-restricted diet showed a decrease in triglyceride levels. Additionally, low glyceimic-load diets were shown to be as effective as low-fat diets to achieve weight loss. This was associated with decreased triglyceride levels and increased HDL. It is important to note that children who followed a low-carb diet had reduced triglyceride levels whether they lost weight or not. This is helpful because it may reduce pressure of patients to lose weight and simply allow them to focus on the nutritional approach to treating CO. In general, a combined diet and activity approach to weight loss is successful in managing CD. It is important to ensure compliance and comfort with the weight loss approach for adolescents. If activity levels decline, the study shows that a focus on nutrition can still improve the health of the adolescent.

Rae-Ellen W. Kavey. Combined dyslipidemia in childhood, Journal of Clinical Lipidology, Volume 9, Issue 5, Supplement,
2015, Pages S41-S56, ISSN 1933-2874, https://doi.org/10.1016/j.jacl.2015.06.008.

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Joe Devine: Genetic and microbiome influence on lipid metabolism and dyslipidemia

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Joe Devine: Genetic and microbiome influence on lipid metabolism and dyslipidemia

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This study looks at the microbiome and genetic factors involving dylipeidemia. Since dyslipidemia is a predictor of cardiovascular probems and obesity genetic risk factors would be  in play. However, the study shows that there is a large variance between individuals based on 150 loci (determining ~40% of the variance) are attributable to abnormal lipid metabolism. The gut microbiome which is a symbiotic relationship between host and microorganisms coproduce enzymes that help to regulate multiple digestive pathways including the regulation of lipid levels. The gut microbiome regulates lipid metabolism through the SCFAs and CLAs which can be produced by microorganisms in the microbiome. In the animal models that mice that were supplemented with Bifidobacterium spp. and Lactobacillus plantarum had less circulating TG, LDL, and TC, and had higher levels of HDL present. Conversely, L. plantarum and Lactobacillus curvatus supplementation led to the opposite effect. These animal models experiments highlight that treatment of the microbiome could have an effect and be a possible treatment for the metabolism lipids.

Matey-Hernandez, M. L., Williams, F., Potter, T., Valdes, A. M., Spector, T. D., & Menni, C. (2018). Genetic and microbiome influence on lipid metabolism and dyslipidemia. Physiological genomics, 50(2), 117–126. https://doi.org/10.1152/physiolgenomics.00053.2017

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The Role of Nutraceuticals in the Optimization of Lipid-Lowering Therapy in High-Risk Patients with Dyslipidaemia

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The Role of Nutraceuticals in the Optimization of Lipid-Lowering Therapy in High-Risk Patients with Dyslipidaemia

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Post by Mitchell Watts

This review summarizes recent guidelines and research relating to the use of nutraceuticals in the management of individuals at high risk of atherosclerotic cardiovascular disease.

In brief, they reviewed the following neutraceuticals: Icosapent ethyl (EPA), L-Carnitine, Coenzyme Q-10, plant sterols and stanols, red yeast rice, bergamot, berberine, polyunsaturated omega-3 fatty acids, Vitamin D, and Armolipid Plus (which contains berberine, red yeast rice, monacolin K, policosanol, coenzyme Q10, astaxanthin, and folic acid). Some of the benefits they listed are as follows: managing residual risk associated with lipids other than LDL-C, managing non-lipid-mediated residual risk, optimizing LDL-C treatment for patients with statin intolerance, optimizing LCL-C treatment when add-on therapies for statins are not available. Also, all these nutraceuticals may be adjuncts to lifestyle management for individuals at high risk of ASCVD.

What I found interesting is that this review cited two large placebo-controlled randomized control trials with fish oil supplementation with EPA and DHA, and no significant difference was found between the treatment and placebo groups with respect to vascular event risk reduction. This is despite using AHA recommended dosing of EPA and DHA. However, there was one RCT (REDUCE-IT) that used a substantially larger dose (4g) of highly purified EPA (icosapent ethyl). Supplementation with icosapent ethyl led to a 25% relative reduction in first events of a cardiovascular outcomes, and was also found to reduce subsequent and total ischemic events. Therefore, the dose and composition of PUFA preparations is important in determining vascular outcomes.

Clinically, while there are many lipid-lowering medications, nutraceuticals may play an important role in ASCVD management, particularly in statin intolerant patients.

Penson, P. E., & Banach, M. (2020). The Role of Nutraceuticals in the Optimization of Lipid-Lowering Therapy in High-Risk Patients with Dyslipidaemia. Current atherosclerosis reports, 22(11), 67.

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doi: 10.1007/s11883-020-00887-z.

Affiliations

¹ School of Pharmacy and Biomolecular Sciences, Liverpool John Moores University, Liverpool, UK.

² Liverpool Centre For Cardiovascular Science, Liverpool, UK.

³ University of Liverpool, Liverpool, UK.

⁴ Department of Hypertension, Medical University of Lodz, Rzgowska 281/289, 93-338, Lodz, Poland. maciejbanach77@gmail.com.

⁵ Polish Mother's Memorial Hospital Research Institute (PMMHRI), Lodz, Poland. maciejbanach77@gmail.com.

⁶ Cardiovascular Research Centre, University of Zielona Gora, Zielona Gora, Poland. maciejbanach77@gmail.com.

Free PMC article

Free PMC article

doi: 10.1007/s11883-020-00887-z.

Affiliations

¹ School of Pharmacy and Biomolecular Sciences, Liverpool John Moores University, Liverpool, UK.

² Liverpool Centre For Cardiovascular Science, Liverpool, UK.

³ University of Liverpool, Liverpool, UK.

⁴ Department of Hypertension, Medical University of Lodz, Rzgowska 281/289, 93-338, Lodz, Poland. maciejbanach77@gmail.com.

⁵ Polish Mother's Memorial Hospital Research Institute (PMMHRI), Lodz, Poland. maciejbanach77@gmail.com.

⁶ Cardiovascular Research Centre, University of Zielona Gora, Zielona Gora, Poland. maciejbanach77@gmail.com.

Abstract

Purpose of review: We aimed to summarize recent guidelines, position papers, and high-quality clinical research relating the use of nutraceuticals in the management of individuals at high risk of atherosclerotic cardiovascular disease.

Recent findings: It is essential that individuals at high risk of cardiovascular disease receive guideline-directed evidence-based therapies to reduce their risk of morbidity and mortality from cardiovascular events. Compared with conventional therapeutics, nutraceuticals have undergone relatively little investigation in randomized controlled trials. Thus, recommendations for nutraceuticals in international guidelines are rare, and nutraceuticals should not be used preferentially in place of statins. Nevertheless, recent position papers from the International Lipid Expert Panel and clinical evidence from studies of triglyceride reduction by polyunsaturated fatty acid administration demonstrate that nutraceuticals do have an important role in optimizing therapy in individuals at high risk of cardiovascular disease. Roles for nutraceuticals include as follows: (1) managing residual risk associated with lipids other than low-density lipoprotein cholesterol (LDL-C); (2) managing non-lipid-mediated residual risk; (3) optimizing LDL-C treatment in statin intolerance; (4) optimizing LCL-C treatment when add-on therapies for statins are not available; (5) as adjuncts to lifestyle for individuals at high lifetime risk of atherosclerotic cardiovascular disease (ASCVD). The strength of evidence for each of these applications is variable. In addition to guideline-directed therapeutics, nutraceuticals may have roles in optimizing preventative therapy and targeting residual risk in individuals at high risk of ASCVD. Application of Good Manufacturing Practice and randomized controlled trials when producing and evaluating nutraceuticals will expand the armoury of evidence-based agents for the prevention of ASCVD.

Keywords: Efficacy; Lipid disorders; Nutraceuticals; Safety; Therapy.

Conflict of interest statement

owns four shares in AstraZeneca PLC and has received honoraria and/or travel reimbursement for events sponsored by AKCEA, Amgen, AMRYT, Link Medical, Napp, and Sanofi; , speakers bureau: Abbott/Mylan, Abbott Vascular, Actavis, AKCEA, Amgen, Biofarm, KRKA, MSD, Polpharma, Sanofi-Aventis, Servier, and Valeant; consultant to Abbott Vascular, AKCEA, Amgen, Daichii Sankyo, Esperion, Freia Pharmaceuticals, Lilly, MSD, Polfarmex, Resverlogix, and Sanofi-Aventis; and grants from Sanofi and Valeant.

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DeFelice SL. The nutraceutical revolution - its impact on food-industry R-and-D. Trends Food Sci Technol. 1995;6(2):59-61. doi: 10.1016/S0924-2244(00)88944-X. - DOI

Mazza G Functional foods: biochemical and processing aspects. CRCs; 1998.

World Health Organization. World Health Statistics 2018: monitoring health for the SDGs 2018.

Gofman JW, Young W, Tandy R. Ischemic heart disease, atherosclerosis, and longevity. Circulation. 1966;34(4):679-697. doi: 10.1161/01.cir.34.4.679. - DOI - PubMed

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anticholesteremic agents / therapeutic use*

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national center for biotechnology information

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The Role of Nutraceuticals in the Optimization of Lipid-Lowering Therapy in High-Risk Patients with Dyslipidaemia - PubMed

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doi: 10.1007/s11883-020-00887-z. 1 School of Pharmacy and Biomolecular Sciences, Liverpool John Moores University, Liverpool, UK. 2 Liverpool Centre For Cardiovascular Science, Liverpool, UK. 3 University of Liverpool, Liverpool, UK. 4 Department of Hypertension, Medical University of Lodz, Rzgowska 281/289, 93-338, Lodz, Poland. maciejbanach77@gmail.com. 5 Polish Mother's Memorial Hospital Research Institute (PMMHRI), Lodz, Poland.

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The effect of apple vinegar consumption on glycemic indices, blood pressure, oxidative stress, and homocysteine in patients with type 2 diabetes and dyslipidemia: A randomized controlled clinical trial.

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The effect of apple vinegar consumption on glycemic indices, blood pressure, oxidative stress, and homocysteine in patients with type 2 diabetes and dyslipidemia: A randomized controlled clinical trial.

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Emalee Haynes
The effect of apple vinegar consumption on glycemic indices, blood pressure, oxidative stress, and homocysteine in patients with type 2 diabetes and dyslipidemia: A randomized controlled clinical trial - PubMed (nih.gov)

This trial followed 70 patients who had hyperlipidemia and type 2 diabetes that were either in a control group or received apple cider vinegar daily over a course of 8 weeks. During this time period the patient's blood pressures, fasting blood glucose, and insulin sensitivity checks that occurred to monitor for a difference. This trial concluded that there were benefits associated with taking apple cider vinegar daily, especially relating to glycemic controls and oxidative stress. The use of apple cider vinegar has been a popular fad recently, and so this trial was important to validate that there can be potential benefits to consumption on a regular basis. Additionally, this could be a possible recommendation for patients who have these disease states, and similar ones too. This is an opportunity to answer patient questions that will appear in a pharmacy setting, and likely worked into other healthcare settings as well. Being knowledgeable about popular fads relating to health care choices is important because as medical professionals we are likely the ones patients will turn to for advice on whether it would be effective for them to try.

Gheflati, Alireza et al. “The effect of apple vinegar consumption on glycemic indices, blood pressure, oxidative stress, and homocysteine in patients with type 2 diabetes and dyslipidemia: A randomized controlled clinical trial.” Clinical nutrition ESPEN vol. 33 (2019): 132-138. doi:10.1016/j.clnesp.2019.06.006

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Dyslipidemia,  malnutrition,  inflammation, cardiovascular  disease  and  mortality  in  chronic kidney  disease - Cole Zetter

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Dyslipidemia,  malnutrition,  inflammation, cardiovascular  disease  and  mortality  in  chronic kidney  disease - Cole Zetter

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For this week's weekly wall I read an article that related Dyslipidemia malnutrition, inflammation, cardiovascular disease and mortality in chronic kidney disease. The previously listed factors are commonly seen and associated in patients that are diagnosed with chronic kidney disease as well as increased mortality. I found this study to be important because it really shed light onto some important facts on dyslipidemia, nutrition, and cardiovascular disease. The article defined dyslipidemia as  a constellation of an abnormal amount of lipids in the blood then later went on to reference specific laboratory ranges of total cholesterol, LDL, and triglycerides for patients with chronic kidney disease. These patients with abnormal levels are at higher risk of developing chronic heart disease when compared to the general population. This is partly because there is a risk relationship defined by cholesterol and cardiovascular disease which is exacerbated with malnutrition and inflammation. One key finding of this study I found was that the article stated that tobacco smoking, insulin resistance, elev-

ated fat mass and hypertension all lead to increased cytokine production, including tumor necrosis factor-alpha, interferon -gamma, IL-1 and IL-6 that reduce the appetite, the intake of calories and proteins, thereby leading to muscle wasting, weight loss, decreased serum albumin, lymphopenia and

low cholesterol levels. These effects only advance atherosclerosis, which is deposition of plaques of fatty materials within the arteries. The clinical implications of this study would be that dyslipidemia poses a greater risk for cardiovascular disease in the late stages of chronic kidney disease. To combat this, malnutrition and inflammation need to be combated as well with healthy lifestyle and nutrition choices as well as strong healthcare plan.

Peev, Vasil, Ali Nayer, and Gabriel Contreras. “Dyslipidemia, Malnutrition, Inflammation, Cardiovascular Disease and Mortality in Chronic Kidney Disease.” Current opinion in lipidology 25.1 (2014): 54–60. Web.

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Seonwook Kim: Efficacy of tomato concentrates in mouse models of dyslipidemia and cancer

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Seonwook Kim: Efficacy of tomato concentrates in mouse models of dyslipidemia and cancer

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My selected article is the efficacy of tomato concentrate in the western diet mouse model. It has been reported that dietary lycopene has beneficial effects to control lipid levels. And tomato and tomato products are the major sources of lycopene compounds in the human diet. And this study group previously reported how freeze-dried tomato powder ameliorated dyslipidemia and atherosclerosis. And this study investigated more concentrated tomato extract to check the doses for human application. This study group used transgenic tomatoes for the experiments. The key finding in this study is that tomato concentrate treatment in the dyslipidemia mouse model significantly reduced total cholesterol and triglyceride. This study provides a simple and economical means of dramatically concentrating an apoA-I mimetic peptide produced in transgenic tomatoes that makes testing oral apoA-I therapy in humans a feasible strategy. In clinical approaches, it can be used as an additional supplement for dyslipidemia patients to ameliorate the high level of lipid VLDL and LDL circulation.

Chattopadhyay A, Grijalva V, Hough G, Su F, Mukherjee P, Farias-Eisner R, Anantharamaiah GM, Faull KF, Hwang LH, Navab M, Fogelman AM, Reddy ST. Efficacy of tomato concentrates in mouse models of dyslipidemia and cancer. Pharmacol Res Perspect. 2015 Aug;3(4):e00154. doi: 10.1002/prp2.154. Epub 2015 Jun 24. PMID: 26171234; PMCID: PMC4492730.

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Affiliations

¹ Division of Cardiology, Department of Medicine, David Geffen School of Medicine at UCLA Los Angeles, California, 90095-1736.

² Department of Obstetrics and Gynecology, David Geffen School of Medicine at UCLA Los Angeles, California, 90095-1736.

³ Department of Medicine, University of Alabama at Birmingham Birmingham, Alabama, 35294.

⁴ Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine at UCLA Los Angeles, California, 90095-1736.

⁵ Division of Cardiology, Department of Medicine, David Geffen School of Medicine at UCLA Los Angeles, California, 90095-1736 ; Department of Obstetrics and Gynecology, David Geffen School of Medicine at UCLA Los Angeles, California, 90095-1736 ; Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at UCLA Los Angeles, California, 90095-1736.

Free PMC article

Free PMC article

Affiliations

¹ Division of Cardiology, Department of Medicine, David Geffen School of Medicine at UCLA Los Angeles, California, 90095-1736.

² Department of Obstetrics and Gynecology, David Geffen School of Medicine at UCLA Los Angeles, California, 90095-1736.

³ Department of Medicine, University of Alabama at Birmingham Birmingham, Alabama, 35294.

⁴ Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine at UCLA Los Angeles, California, 90095-1736.

⁵ Division of Cardiology, Department of Medicine, David Geffen School of Medicine at UCLA Los Angeles, California, 90095-1736 ; Department of Obstetrics and Gynecology, David Geffen School of Medicine at UCLA Los Angeles, California, 90095-1736 ; Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at UCLA Los Angeles, California, 90095-1736.

Abstract

We previously reported that adding freeze-dried tomato powder from transgenic plants expressing the apolipoprotein A-I mimetic peptide 6F at 2.2% by weight to a Western diet (WD) ameliorated dyslipidemia and atherosclerosis in mice. The same dose in a human would require three cups of tomato powder three times daily. To reduce the volume, we sought a method to concentrate 6F. Remarkably, extracting the transgenic freeze-dried tomato overnight in ethyl acetate with 5% acetic acid resulted in a 37-fold reduction in the amount of transgenic tomato needed for biologic activity. In a mouse model of dyslipidemia, adding 0.06% by weight of the tomato concentrate expressing the 6F peptide (Tg6F) to a WD significantly reduced plasma total cholesterol and triglycerides (P < 0.0065). In a mouse model of colon cancer metastatic to the lungs, adding 0.06% of Tg6F, but not a control tomato concentrate (EV), to standard mouse chow reduced tumor-associated neutrophils by 94 ± 1.1% (P = 0.0052), and reduced tumor burden by two-thirds (P = 0.0371). Adding 0.06% of either EV or Tg6F by weight to standard mouse chow significantly reduced tumor burden in a mouse model of ovarian cancer; however, Tg6F was significantly more effective (35% reduction for EV vs. 53% reduction for Tg6F; P = 0.0069). Providing the same dose of tomato concentrate to humans would require only two tablespoons three times daily making this a practical approach for testing oral apoA-I mimetic therapy in the treatment of dyslipidemia and cancer.

Keywords: ApoA-I mimetic peptides; cancer; drug delivery; lipids; transgenic tomatoes.

References

Baranova IN, Kurlander R, Bocharov AV, Vishnyakova TG, Chen Z, Remaley A, et al. Role of CD36 in bacterial recognition, phagocytosis, and pathogen-induced JNK-mediated signaling. J Immunol. 2008;181:7147-7156. - PMC - PubMed

Chang C-L, Hsu H-Y, Lin H-Y, Chiang W, Lee H. Lysophosphatidic acid-induced oxidized low-density lipoprotein uptake is class A scavenger receptor-dependent in macrophages. Prostaglandins Other Lipid Mediat. 2008;87:20-25. - PubMed

Chattopadhyay A, Navab M, Hough G, Gao F, Meriwether D, Grijalva V, et al. A novel approach to oral apoA-I mimetic therapy. J Lipid Res. 2013;54:995-1010. - PMC - PubMed

Cust AE, Kaaks R, Friedenreich C, Bonnet F, Laville M, Tjonneland A, et al. Metabolic syndrome, plasma lipid, lipoprotein and glucose levels, and endometrial cancer risk in the European Prospective Investigation into Cancer and Nutrition (EPIC) Endocr Relat Cancer. 2007;14:755-767. - PubMed

van Duijnhoven FJ, Bueno-De-Mesquita HB, Calligaro M, Jenab M, Pischon T, Jansen EH, et al. Blood lipid and lipoprotein concentrations and colorectal cancer risk in the European Prospective Investigation into Cancer and Nutrition. Gut. 2011;60:1094-1102. - PubMed

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national center for biotechnology information

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Efficacy of tomato concentrates in mouse models of dyslipidemia and cancer - PubMed

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We previously reported that adding freeze-dried tomato powder from transgenic plants expressing the apolipoprotein A-I mimetic peptide 6F at 2.2% by weight to a Western diet (WD) ameliorated dyslipidemia and atherosclerosis in mice. The same dose in a human would require three cups of tomato powder ...

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A randomized, double blind, placebo-controlled, multicenter clinical trial to assess the efficacy and safety of Emblica officinalis extract in patients with dyslipidemia- Esraa Zamzami

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A randomized, double blind, placebo-controlled, multicenter clinical trial to assess the efficacy and safety of Emblica officinalis extract in patients with dyslipidemia- Esraa Zamzami

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The article I chose for this week’s weekly wall talks about the efficacy of Emblica Officinalis extract (Indian gooseberry). The main finding of this randomized, double-blind, and placebo-controlled study is that Emblica officinalis extract showed promising results in improving dyslipidemia. Dyslipidemia is a major risk factor for atherosclerosis, and improving dyslipidemia decreases this risk. This study strongly relates to nutrition because they are using the extract of gooseberry that contains high levels of polyphenols and omega 3 acids, which can contribute to the beneficial effects. Ninety-eight dyslipidemic patients were randomized into two groups. The first group took the Emblica officinalis extract, and the second group took a placebo pill. The intervention group had a significant reduction in total cholesterol, LDL, and triglyceride levels. Another interesting finding of this study is that Emblica officinalis extract did not decrease Co Q10 levels, a major side effect seen in statin therapy. Co Q10 is critical for the respiration of the mitochondria. Emblica Officinalis extract could be a potential therapy that could be safely used for dyslipidemic patients; however, more considerable research should be done.

Upadya, H., Prabhu, S., Prasad, A., Subramanian, D., Gupta, S., & Goel, A. (2019). A randomized, double blind, placebo controlled, multicenter clinical trial to assess the efficacy and safety of Emblica officinalis extract in patients with dyslipidemia. BMC complementary and alternative medicine, 19(1), 27. https://doi.org/10.1186/s12906-019-2430-y

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Randomized Controlled Trial

doi: 10.1186/s12906-019-2430-y.

Affiliations

¹ Aadhitya Adhikari Hospital, Contour Road, Gokulam, Mysore, 570002, India.

² LifeCare Hospital, No.99, OM Complex, 20th Main, Gangothri Circle, BTM 1st Stage, Bangalore, 560029, India.

³ Sri Venkateshwara Hospital, No.86, Hosur Main Road, Madiwala, Bangalore, 560068, India.

⁴ Syncretic Clinical Research Services, No. 4, 5th cross, 11th Main Road, Vasanthnagar, Bangalore, 560052, India.

⁵ Amrita School of Pharmacy, Amrita Institute of Medical Sciences and Research Centre, Amrita Vishwa Vidyapeetham, Kochi, 682041, India. swatigupta@aims.amrita.edu.

⁶ Center for Gastrointestinal Research, Center for Translational Genomics and Oncology, Baylor Scott & White Research Institute and Sammons Cancer Center, Baylor University Medical Center, Dallas, Texas, 3410 Worth Street, Suite 610, Dallas, TX, 75246, USA. Ajay.Goel@BSWHealth.org.

Free PMC article

Randomized Controlled Trial

Free PMC article

doi: 10.1186/s12906-019-2430-y.

Affiliations

¹ Aadhitya Adhikari Hospital, Contour Road, Gokulam, Mysore, 570002, India.

² LifeCare Hospital, No.99, OM Complex, 20th Main, Gangothri Circle, BTM 1st Stage, Bangalore, 560029, India.

³ Sri Venkateshwara Hospital, No.86, Hosur Main Road, Madiwala, Bangalore, 560068, India.

⁴ Syncretic Clinical Research Services, No. 4, 5th cross, 11th Main Road, Vasanthnagar, Bangalore, 560052, India.

⁵ Amrita School of Pharmacy, Amrita Institute of Medical Sciences and Research Centre, Amrita Vishwa Vidyapeetham, Kochi, 682041, India. swatigupta@aims.amrita.edu.

⁶ Center for Gastrointestinal Research, Center for Translational Genomics and Oncology, Baylor Scott & White Research Institute and Sammons Cancer Center, Baylor University Medical Center, Dallas, Texas, 3410 Worth Street, Suite 610, Dallas, TX, 75246, USA. Ajay.Goel@BSWHealth.org.

Abstract

Background: Dyslipidemia is one of the most frequently implicated risk factors for development of atherosclerosis. This study evaluated the efficacy of amla (Emblica officinalis) extract (composed of polyphenols, triterpenoids, oils etc. as found in the fresh wild amla fruit) in patients with dyslipidemia.

Methods: A total of 98 dyslipidemic patients were enrolled and divided into amla and placebo groups. Amla extract (500 mg) or a matching placebo capsule was administered twice daily for 12 weeks to the respective group of patients. The patients were followed up for 12 weeks and efficacy of study medication was assessed by analyzing lipid profile. Other parameters evaluated were apolipoprotein B (Apo B), apolipoprotein A1 (Apo A1), Coenzyme Q10 (CoQ10), high-sensitive C-reactive protein (hsCRP), fasting blood sugar (FBS), homocysteine and thyroid stimulating hormone (TSH).

Results: In 12 weeks, the major lipids such as total cholesterol (TC) (p = 0.0003), triglyceride (TG) (p = 0.0003), low density lipoprotein cholesterol (LDL-C) (p = 0.0064) and very low density lipoprotein cholesterol (VLDL-C) (p = 0.0001) were significantly lower in amla group as compared to placebo group. Additionally, a 39% reduction in atherogenic index of the plasma (AIP) (p = 0.0177) was also noted in amla group. The ratio of Apo B to Apo A1 was reduced more (p = 0.0866) in the amla group as compared to the placebo. There was no significant change in CoQ10 level of amla (p = 0.2942) or placebo groups (p = 0.6744). Although there was a general trend of FBS reduction, the numbers of participants who may be classified as pre-diabetes and diabetes groups (FBS > 100 mg/dl) in the amla group were only 8. These results show that the amla extract used in the study is potentially a hypoglycaemic as well. However, this needs reconfirmation in a larger study.

Conclusions: The Amla extract has shown significant potential in reducing TC and TG levels as well as lipid ratios, AIP and apoB/apo A-I in dyslipidemic persons and thus has scope to treat general as well as diabetic dyslipidemia. A single agent to reduce cholesterol as well as TG is rare. Cholesterol reduction is achieved without concomitant reduction of Co Q10, in contrast to what is observed with statins.

Trial registration: Registered with Clinical Trials Registry- India at www.ctri.nic.in (Registration number: CTRI/2015/04/005682 ) on 8 April 2015 (retrospectively registered).

Keywords: AIP; Cholesterol; Dyslipidemia; Emblica officinalis; TG, CoQ10.

Conflict of interest statement

Ethics approval and consent to participate

The study protocol was approved by respective institutional ethics committees where study was conducted, i.e. Mysore Clinical Research Ethics Committee on 22/2/2015 (study site: Aadhitya Adhikari Hospital, Contour Road, Gokulam, Mysore-570,002), Life Care Hospital Institutional Ethics Commitee on 15/3/2015 (study site: LifeCare Hospital, 99, OM Complex, 20th Main, Gangothri Circle, BTM 1st Stage, Bangalore-560,029), Sri Venkateshwara Hospital Ethics Committee on 15/3/2015 (Study site: Sri Venkateshwara Hospital, No.86, Hosur Main Road, Madiwala, Bangalore- 560,068) and Prashanth Hospital Ethics Committee on 17/3/2015 (study site: Prashanth Hospital, Bommanahalli Circle, Hosur Main Road, Bangalore-560,068) and registered with Clinical Trials Registry- India at www.ctri.nic.in (Registration number: CTRI/2015/04/005682) on 8 April 2015 (retrospectively registered). Any study related activity was undertaken only after subjects voluntarily signed the consent form to participate in the study.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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national center for biotechnology information

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A randomized, double blind, placebo controlled, multicenter clinical trial to assess the efficacy and safety of Emblica officinalis extract in patients with dyslipidemia - PubMed

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Randomized Controlled Trial doi: 10.1186/s12906-019-2430-y. 1 Aadhitya Adhikari Hospital, Contour Road, Gokulam, Mysore, 570002, India. 2 LifeCare Hospital, No.99, OM Complex, 20th Main, Gangothri Circle, BTM 1st Stage, Bangalore, 560029, India. 3 Sri Venkateshwara Hospital, No.86, Hosur Main Road, Madiwala, Bangalore, 560068, India. 4 Syncretic Clinical Research Services, No.

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Impact of Nutrients and Food Components on Dyslipidemias: What Is the Evidence? -Cassie Craig

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Impact of Nutrients and Food Components on Dyslipidemias: What Is the Evidence? -Cassie Craig

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This study is important because it evaluates many different foods/food groups to determine what is helpful in treating dyslipidemias. This treatment would target the development of cardiovascular disease (CVD), more specifically atherosclerosis. As we learned in this week’s lecture, we want low LDL cholesterol levels and high HDL cholesterol levels. This paper addresses food groups in terms of these lipid levels to determine how to maintain healthy levels. It was found that the following nutrients/groups are beneficial in maintaining lipid levels: “monounsaturated and polyunsaturated fatty acids, soluble fiber, vegetable proteins, phytosterols, and polyphenols.” (Rosa et al., 2015) Maintenance of these components in the diet of those with dyslipidemias should help the patient to regulate lipid levels, which relates to nutritional sciences. Clinical implications of this study would include the recommendation, from a physician, of certain nutritional components into the patients’ diets to combat the risk of CVD. The components listed above should be recommended to patients by encouraging consumption of fruits, vegetables, antioxidants, oats, and nuts.

Rosa, Carla de Oliveira Barbosa et al. “Impact of nutrients and food components on dyslipidemias: what is the evidence?.” Advances in nutrition (Bethesda, Md.) vol. 6,6 703-11. 13 Nov. 2015, doi:10.3945/an.115.009480

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Aerobic Exercise and Lipid Levels- Cole Cincinelli

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Aerobic Exercise and Lipid Levels- Cole Cincinelli

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Dyslipidemia is a risk of coronary heart disease. This risk can be lowered by exercise which can improve blood lipid profiles. A high concentration of low-density-lipoproteins(LDL) within circulation could lead to atherosclerosis, a buildup of LDL proteins which obstruct blood vessels. An obstruction of coronary vessels leads to a heart attack. The results of these studies suggest that exercise time, exercise volume and exercise intensity all have a positive effect on blood lipid concentrations. To reduce LDL and TG levels, it is necessary to increase the aerobic exercise intensity. Sometimes this is difficult to achieve in individuals with coronary artery disease who are of limited exercise capacity or other risk factors. Clinicians may be excessively reliant on lipid-lowering drugs (statins) to treat patients with dyslipidemias. Clinicians should encourage aggressive lifestyle alterations, such as exercise. Not only can this prevent and treat dyslipidemia but also will reduce the risks of heart attack.

Wang Y, Xu D. Effects of aerobic exercise on lipids and lipoproteins. Lipids Health Dis. 2017;16(1):132. Published 2017 Jul 5. doi:10.1186/s12944-017-0515-5

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Katelyn Spain: Effects of Smoking and Smoking Cessation on Lipids and Lipoproteins: Outcomes from a Randomized Clinical Trial

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Katelyn Spain: Effects of Smoking and Smoking Cessation on Lipids and Lipoproteins: Outcomes from a Randomized Clinical Trial

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The purpose of this study was to determine the effects of smoking cessation on lipoproteins. This study was a double-blind, randomized, placebo one-year clinical study to test the effects of five different smoking cessation pharmacotherapies. Lipoprotein profiles were taken before the trial started, as baseline, and one year after smoking cessation. It was found that around 37% of smokers who entered the clinical trial, successfully quit smoking. This group was found to have gained more weight over the course of the year. However, even with more weight gain than those who were not successful in smoking cessation, those who successfully quit had an increase in HDL cholesterol present. It was found that smoking cessation has no significant change in LDL levels. One interesting finding was that these results were stronger in women than men. As for clinical implications of this study, smoking cessation can increase HDL levels in the body. Physicians who have patients that do smoke can relay this as one of the benefits of smoking cessation, which can aid in reducing cardiovascular disease risks.

Gepner, A. D., Piper, M. E., Johnson, H. M., Fiore, M. C., Baker, T. B., & Stein, J. H. (2011). Effects of smoking and smoking cessation on lipids and lipoproteins: outcomes from a randomized clinical trial. American heart journal, 161(1), 145–151. https://doi.org/10.1016/j.ahj.2010.09.023

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Effects of Smoking and Smoking Cessation on Lipids and Lipoproteins: Outcomes from a Randomized Clinical Trial

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The effects of smoking and smoking cessation on lipoproteins have not been studied in a large contemporary group of smokers. This study was designed to determine the effects of smoking cessation on lipoproteins.One-year, prospective, double-blind, randomized, ...

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Ivana Djuricic: Dyslipidemia and Omega3 Fatty Acids

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Ivana Djuricic: Dyslipidemia and Omega3 Fatty Acids

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Masuda D, Miyata Y, Matsui S, Yamashita S. Omega-3 fatty acid ethyl esters improve low-density lipoprotein subclasses without increasing low-density lipoprotein-cholesterol levels: A phase 4, randomized study. Atherosclerosis. 2020 Jan;292:163-170. doi: 10.1016/j.atherosclerosis.2019.11.014. Epub 2019 Nov 19. PMID: 31809985.

Dyslipidemia is one of the cardiometabolic risk factors for developing metabolic disease and is also a risk factor for cardiovascular disease (CVD), which is a major cause of death. This paper looks at a phase 4 study done to see what effects omega-3 has on the lipid profile of people with dyslipidemia and is important because shifting the lipid profile away from small LDLs—which have lower affinity toward the LDL receptor and an easier time getting into artery walls to form atherosclerotic plaques—and toward larger, more buoyant LDLs and/or the denser HDLs would improve dyslipidemia, lowering the risk for CVD, and improving quality of life.

One of the key findings is that, although HDL did not appear to be affected, there was a significant increase in LDL particle size and decrease in LDL-C concentration in the treatment group (given omega-3) than the control at week 8 of the study.

With regard to nutrition and the clinical implications of this study, it is further evidence that perhaps patients would benefit from the implementation of a Mediterranean diet plan that focuses on omega-3 fatty acids, in addition to decreasing saturated fats and increasing soluble fiber, as a treatment plan for complex metabolic syndromes where one of the underlying risk factors is dyslipidemia.

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Posted by Richard Proudfoot

The research paper selected for this week is titled: “Associations of fats and carbohydrate intake with cardiovascular disease and mortality in 18 countries from five continents (PURE): a prospective cohort study” This August 29, 2017, article was published online in the Lancet 2017; 39o: 2050-62. The authors are Mahshid Dehghan, Andrew Mente, Xiaohe Zhang, Sumathi Swaminathan, Wei Li, Viswanathan Mohan, Romaina Iqbal, Rajesh Kumar, Edelweiss Wentzel-Viljoen, Annika Rosengren, Leela Itty Amma, Alvaro Avezum, Jephat Chifamba, Rafael Diaz, Rasha Khatib, Scott Lear, Patricio Lopez-Jaramillo, Xiaoyun Liu, Rajeev Gupta, Noushin Mohammadifard, Nan Gao, Aytekin Oguz, Anis Safura Ramli, Pamela Seron, Yi Sun, Andrzej Szuba, Lungiswa Tsolekile, Andreas Wielgosz, Rita Yusuf, Afzal Hussein Yusufali, Koon K Teo, Sumathy Rangarajan, Gilles Dagenais, Shrikant I Bangdiwala, Shofiqul Islam, Sonia S Anand, Salim Yusuf, on behalf of the Prospective Urban Rural Epidemiology (PURE) study investigators.

The Prospective Urban Rural Epidemiology (PURE) study is a large, epidemiological cohort study of individuals aged 35–70 years (enrolled between Jan 1, 2003, and March 31, 2013) in 18 countries with a median follow-up of 7.4 years (IQR 5·3–9·3). The dietary intake of 135 335 individuals was recorded using validated food frequency questionnaires. The primary outcomes were total mortality and major cardiovascular events (fatal cardiovascular disease, non-fatal myocardial infarction, stroke, and heart failure). Secondary outcomes were all myocardial infarctions, stroke, cardiovascular disease mortality, and non-cardiovascular disease mortality. The Participants were categorized into quintiles of nutrient intake (carbohydrate, fats, and protein) based on the percentage of energy provided by nutrients. The authors assessed the associations between consumption of carbohydrates, total fat, and each type of fat with cardiovascular disease and total mortality. The investigators calculated hazard ratios using a multivariable Cox frailty model.

This study is important because the findings from 18 less industrialized countries on 5 continents differed significantly from previous North American and Europe countries' studies.

The key findings from this study are that high carbohydrate intake was associated with a higher risk of total mortality, whereas total fat and types of fat were related to lower total mortality. Total fat and types of fat were not associated with cardiovascular disease, myocardial infarction, or cardiovascular disease mortality, whereas saturated fat had an inverse association with stroke (more saturated fat quintile was associated with less incidence of stroke and vice versa.)

The clinical implication of this study does not support the old recommendation to limit total fat intake to less than 30% of energy and current recommendations to limit saturated fat intake to less than 10% of energy. Individuals with high carbohydrate intake might benefit from a reduction in carbohydrate intake and an increase in the consumption of fats. This PURE study findings also suggest that predicting the net clinical effect based on considering only the effects of nutrient intake on LDL cholesterol is not reliable in projecting the effects of diet on cardiovascular disease events or on total mortality.

Dehghan M, Mente A, Zhang X, et al. Associations of fats and carbohydrate intake with cardiovascular disease and mortality in 18 countries from five continents (PURE): a prospective cohort study. Lancet. 2017;390(10107):2050-2062. doi:10.1016/S0140-6736(17)32252-3

https://pubmed.ncbi.nlm.nih.gov/28864332/

Posted by Richard Proudfoot

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Comparison of the efficacy of cardamom (Elettaria cardamomum) with pioglitazone on dexamethasone‐induced hepatic steatosis, dyslipidemia, and hyperglycemia in albino rats

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Comparison of the efficacy of cardamom (Elettaria cardamomum) with pioglitazone on dexamethasone‐induced hepatic steatosis, dyslipidemia, and hyperglycemia in albino rats

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This study is important because it presents a typical cooking spice that may be helpful in treating dyslipidemia. In this study they looked at using cardamom to treat hepatic steatosis, hyperglycemia, and dyslipdemia in albino rats. After completing a lipid profile they found an over all decrease in total cholesterol and triglycerides  but an increase in HDL. They concluded that including cardamom in a patients diet may be useful for decreasing lipidemia. This relates to nutritional science because this is a spice that anyone can purchase from the grocery store and is mainly used in Indian dishes. This has great clinical implications because this makes it more accessible and affordable to the patient. They can easily pick this up and incorporate it into their diet. I believe it is important to educate patients and let them know this may not fix the entirety of the issue it may assist in helping to reduce dyslipidemia, but this isn't an end all solution. -By Ashley Wahlman

Bhat, G. M. N., Nayak, N., Vinodraj, K., Chandralekha, N., Mathai, P., & Cherian, J. (2015). Comparison of the efficacy of cardamom (Elettaria cardamomum) with pioglitazone on dexamethasone-induced hepatic steatosis, dyslipidemia, and hyperglycemia in albino rats. Journal of Advanced Pharmaceutical Technology & Research, 6(3), 136–140. https://doi-org.ezproxy.uky.edu/10.4103/2231-4040.157981

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Abstract

To evaluate the efficacy of cardamom with pioglitazone on dexamethasone-induced hepatic steatosis, dyslipidemia, and hyperglycemia in albino rats. There were four groups of 6 rats each. First group received dexamethasone alone in a dose of 8 mg/kg intraperitoneally for 6 days to induce metabolic changes and considered as dexamethasone control. Second group received cardamom suspension 1 g/kg/10 mL of 2% gum acacia orally 6 days before dexamethasone and 6 days during dexamethasone administration. Third group received pioglitazone 45 mg/kg orally 6 days before dexamethasone and 6 days during dexamethasone administration. Fourth group did not receive any medication and was considered as normal control. Fasting blood sugar, lipid profile, blood sugar 2 h after glucose load, liver weight, liver volume were recorded, and histopathological analysis was done. The effects of cardamom were compared with that of pioglitazone. Dexamethasone caused hepatomegaly, dyslipidemia and hyperglycemia. Both pioglitazone and cardamom significantly reduced hepatomegaly, dyslipidemia, and hyperglycemia ( P < 0.01). Reduction of blood sugar levels after glucose load was significant with pioglitazone in comparison to cardamom ( P < 0.01). Cardamom has comparable efficacy to pioglitazone in preventing dexamethasone-induced hepatomegaly, dyslipidemia, and fasting hyperglycemia.

Keywords: Anti-diabetic, cardamom, insulin resistance, type 2 diabetes mellitus

INTRODUCTION

Over the past three decades, the number of people with diabetes mellitus has more than doubled globally, making it one of the most important public health challenges to all nations. Type 2 diabetes mellitus (T2DM) and pre-diabetes are increasingly observed among children, adolescents, and younger adults. The causes of the epidemic of T2DM are embedded in a very complex group of genetic and epigenetic systems interacting within an equally complex societal framework that determines the behavior and environmental influences. Prevention of T2DM is a "whole-of-life" task and requires an integrated approach operating from the origin of the disease.[ 1] Insulin resistance in muscle, liver, and fat is a prominent feature of most patients with T2DM and obesity, resulting in a reduced response of these tissues to insulin.[ 2]

Currently, a number of synthetic hypolipidemic drugs are available and are effective, but they are associated with severe side effects. Therefore, alternative approaches are eagerly needed, and plant-based therapies attract much interest, as they are effective in reducing lipid levels and show minimal or no side effects. Oral administration of cardamom extract significantly reduced total cholesterol, high-density lipoprotein (HDL), low-density lipoprotein, and very low density lipoprotein and triglycerides in Wistar rats.[ 3]

MATERIALS AND METHODS

Preparation of cardamom powder suspension

Dry cardamom seeds were procured from the market. They were made into a fine powder with the help of a pulverizer. This fine powder was taken in a mortar. 2% gum acacia was added little by little and triturated continuously to obtain the suspension.

Experimental animal

Healthy adult rats of Wistar strain weighing around 240-270 g were used in the present study. The animals were housed in clean polypropylene cages and maintained in a well-ventilated temperature controlled animal house with constant 12 h light/dark schedule. The animals were fed with standard rat pellet diet and clean drinking water was made available ad libitum. All animal procedures have been approved and a prior permission from the Institutional Animal Ethical Committee (IAEC) was obtained as per prescribed guidelines with ethical clearance number KSHEMA/IAEC/04/2012.

Induction of hepatic steatosis, dyslipidemia, and hyperglycemia

Hepatic steatosis, dyslipidemia and hyperglycemia were induced according to the procedure described by Shalam et al.[ 4]

Experimental methods

A total of 24 rats were divided into four groups with 6 rats in each group. Body weight was checked for all groups on day 1, day 7, and on day 12.

First group received dexamethasone alone in a dose of 8 mg/kg intraperitoneally for 6 days to induce metabolic changes and considered as dexamethasone control.

Second group received cardamom powder suspension in 2% gum acacia 1 g/kg/10 ml, oral, 6 days before, and 6 days during dexamethasone administration.

Third group received pioglitazone 45 mg/kg orally, 6 days before dexamethasone, and 6 days during dexamethasone administration.

Fourth group did not receive any medication and was considered as normal control.

Rats were fasted overnight; blood was collected by retro-orbital sinus puncture for fasting blood sugar, lipid profile, and 2 h after a glucose load of 2 g/10 ml/kg IP (postprandial blood sugar). Rats were sacrificed by cervical dislocation. Liver was dissected out, liver weight, liver volume were measured. Livers were stored in 10% formalin and sent for histopathological analysis. The details of the study method are given in Table 1 .

Table 1

Statistical analysis

Data management was done in excel after cleaning and coding. Then the data were transferred to SPSS package (SPSS Inc. Released 2008. SPSS Statistics for Windows, Version 17.0. Chicago: SPSS Inc.) for analysis. The values presented as mean ± standard deviation. Independent t-test was used to compare between two groups. ANOVA with Scheffe's post-hoc test was done for multiple comparisons. A value of P < 0.01 was considered statistically significant.

RESULTS

Effect of cardamom on blood sugar levels in rats

The blood sugar levels of four groups are presented in Table 2 . An increase in blood sugar levels was seen in the dexamethasone group as compared to the normal group. A significant decrease in the fasting and postprandial blood glucose levels was observed in the cardamom and pioglitazone-treated groups as compared to dexamethasone control group ( P < 0.01). The fasting blood glucose levels in the cardamom-treated group was comparable to pioglitazone group ( P = 0.486). A corresponding significant decrease in postprandial blood glucose levels was observed ( P < 0.01) in the pioglitazone group as compared with cardamom group.

Table 2

Effect of cardamom on lipids

The lipid profiles of four groups are presented in Table 2 . An increase in total cholesterol, triglycerides, and decrease in HDL was seen in the dexamethasone group as compared to the normal group. A significant decrease in the total cholesterol and triglyceride, and increase in HDL levels was observed in the cardamom and pioglitazone-treated groups as compared to dexamethasone control group ( P < 0.01). The total cholesterol, triglyceride, and HDL levels in the cardamom-treated group was comparable to pioglitazone group ( P = 0.098, 0.154, and 0.312).

Effect of cardamom on liver weight and liver volume

The liver weight and liver volume of four groups are presented in Table 3 . An increase in the liver weight and liver volume was seen in the dexamethasone group as compared to the normal group. A significant decrease in the liver weight and liver volume was observed in the cardamom and pioglitazone-treated groups as compared to dexamethasone control group ( P < 0.01). The liver weight and liver volume in the cardamom-treated group were comparable to pioglitazone group ( P = 0.248, P = 0.095).

Table 3

Effect of cardamom on body weight

The body weights of four groups are presented in Table 3 . There was a weight loss seen in the dexamethasone group as compared to on day 12. A significant increase in the body weight was observed in the cardamom- and pioglitazone-treated groups as compared to dexamethasone control group ( P < 0.01). The body weight in the cardamom-treated group was comparable to pioglitazone group ( P = 0.304).

Histopathological observations

As depicted in Figure 1 , the Normal control group rats showed normal hepatocytes. The dexamethasone-treated group showed an increase in the size of hepatocytes, cytoplasm is vesicular to clear. Fat deposition was observed. The hepatocytes in rats treated with pioglitazone and cardamom were smaller in size and had reduced fat deposition compared to dexamethasone-treated group.

DISCUSSION

Cardamom ( Elettaria cardamomum) in a dose of 3 g in 2 divided doses per day over 3 months reduced systolic, diastolic and mean blood pressure, increased fibrinolytic activity, and enhanced antioxidant status in a study of newly diagnosed individuals with primary hypertension of stage 1.[ 5] In vitro studies have demonstrated the anti-inflammatory and immunomodulatory effects of cardamom.[ 6] An in vitro study of aqueous extract of cardamom on human platelets showed a protective effect on platelet aggregation and lipid peroxidation.[ 7] Cardamom is used along with chickpea and barley as a traditional herbal medicine for the treatment of diabetes.[ 8] A US patent mentions the use of polyherbal preparations containing cardamom for use in diabetes.[ 9] These features made us to look for any beneficial effect on glucocorticoid-induced metabolic syndrome.

Glucocorticoids are used in a broad spectrum of anti-inflammatory and immunosuppressive therapies, which include allergic and hematological disorders, and renal, intestinal, liver, eye, and skin diseases. Rheumatic diseases and bronchial asthma are the main indications of long-term therapy with these hormones. In addition, glucocorticoids are also used in the suppression of the host-versus-graft or graft-versus-host reactions following organ transplantation surgery.[ 10] Glucocorticoids, as endogenous hormones and prevalent anti-inflammatory and immunosuppressive drugs, have been reported to induce Cushing's syndrome, which is characterized by central obesity and insulin resistance.[ 11] In addition, chronic treatment with synthetic glucocorticoids like dexamethasone has been associated with hyperinsulinemia in both animal and human research[ 12, 13] elevation of 11β- hydroxysteroid dehydrogenase type 1 (HSD1) and an increased generation of cortisol from cortisone in skeletal muscle[ 14] and adipose tissue[ 15] have also been identified in obese insulin-resistant humans, although plasma concentration of cortisol is not above the normal range. In transgenic mice, hepatic 11β-HSD1 overexpression shows a modest insulin resistance, dyslipidemia, and hypertension, but no obesity.[ 16] The effects of selective adipose overexpression are more pronounced, with these animals demonstrating symptoms typically seen with the metabolic syndrome.[ 17]

Nonalcoholic fatty liver disease (NAFLD) is emerging as an important cause of liver disease in India. Epidemiological studies suggest the prevalence of NAFLD in around 9-32% of the general population in India with higher prevalence in those with overweight or obesity and those with diabetes or prediabetes. There is a high prevalence of insulin resistance and nearly half of Indian patients with NAFLD have evidence of full-blown metabolic syndrome. Oxidative stress is involved in the pathogenesis of NAFLD/nonalcoholic steatohepatitis (NASH).[ 18]

Nonalcoholic fatty liver disease is considered as the hepatic manifestation of the metabolic syndrome, which is defined by the presence of central obesity, insulin resistance, hyperlipidemia, hyperglycemia, and hypertension.[ 19] The release of fatty acids from dysfunctional and insulin-resistant adipocytes results in lipotoxicity, caused by the accumulation of triglyceride-derived toxic metabolites in ectopic tissues (liver, muscle, pancreatic beta cells) and subsequent activation of inflammatory pathways, cellular dysfunction, and lipoapoptosis. The cross talk between dysfunctional adipocytes and the liver involves multiple cell populations, including macrophages and other immune cells that in concert promote the development of lipotoxic liver disease, a term that more accurately describes the pathophysiology of NASH.

Metformin was first used in medical practice in the 1950s and has been considered the first-line treatment of type 2 diabetes after receiving approval by the US Food and Drug Administration in 1994. Metformin belongs to a class of insulin sensitizer drugs and acts through reducing hepatic glucose output, increasing insulin-stimulated glucose uptake in peripheral tissue and stimulating fatty acid oxidation in adipose tissue.[ 20] Thiazolidinediones (TZDs) are a class of oral anti-diabetic drugs that induce a nuclear transcription factor, peroxisome proliferator-activated receptor-γ (PPAR-γ), by binding selective ligands.[ 21] PPAR-γ is predominantly expressed in adipose tissue and leads to decreased hepatic fat content and improves glycemic control with insulin sensitivity. TZDs also increase plasma adiponectin levels, activate AMP-activated protein kinase, and induce fatty acid stimulation.[ 22] Rosiglitazone which was used like pioglitazone as insulin sensitizing agent in type 2 diabetes has been banned in several countries due to its cardiovascular side effects.[ 23] Retrospective evaluations have increasingly linked pioglitazone to a higher risk of bladder cancer that appears to be time- and dose-dependent. Pioglitazone remains a medication appropriate for consideration in the management of T2DM; however, clinicians and patients should weigh its risks compared with alternatives, with a regular review of risks.[ 24]

Treatments that rescue the liver from lipotoxicity by restoring adipose tissue insulin sensitivity (e.g., significant weight loss, exercise, TZDs) or preventing activation of inflammatory pathways and oxidative stress (i.e., Vitamin E, TZDs) hold promise in the treatment of NAFLD, although their long-term safety and efficacy remain to be established.[ 25] Pioglitazone reverses NASH and improves liver histology by its effect of increasing adiponectin levels.[ 26] Oxidative stress is believed to play a key role in the pathogenesis of NASH and other liver diseases. Vitamin E is currently the most widely assessed antioxidant. Altered lipid metabolism is thought to be central to the pathogenesis of liver injury in NASH. Therefore, lipid-lowering drugs are attractive therapeutic tools in the treatment of NAFLD.[ 27]

Present study is done to compare the effects of cardamom with that of pioglitazone, on dexamethasone-induced hyperglycemia, dyslipidemia, and hepatic steatosis. Cardamom was as effective as pioglitazone in reducing dyslipidemia, hepatic steatosis, and fasting hyperglycemia. The antioxidant and hypolipidemic effects of cardamom may be partially responsible for the beneficial effects. It is concluded that the administration of cardamom or the use of cardamom in diet might be useful in dyslipidemia, hepatic steatosis, and fasting hyperglycemia due to glucocorticoids excess.

ACKNOWLEDGMENTS

The authors acknowledge sincere thanks to the Department of pharmacology (K.S. Hegde Medical Academy), Nitte University Central Research Laboratory and the staff of animal house for the facilities granted for the research work.

Footnotes

Source of Support: Nil

Conflict of Interest: Nil.

REFERENCES

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Comparison of the efficacy of cardamom (Elettaria cardamomum) with pioglitazone on dexamethasone-induced hepatic steatosis, dyslipidemia, and hyperglycemia in albino rats

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To evaluate the efficacy of cardamom with pioglitazone on dexamethasone-induced hepatic steatosis, dyslipidemia, and hyperglycemia in albino rats. There were four groups of 6 rats each. First group received dexamethasone alone in a dose of 8 mg/kg intraperitoneally for 6 days to induce metabolic changes and considered as dexamethasone control.