Abstract
Bempedoic acid (ETC-1002, 8-hydroxy-2,2,14,14-tetramethylpentadecanedioic acid) is a novel low-density lipoprotein cholesterol-lowering compound. In animals, bempedoic acid targets the liver where it inhibits cholesterol and fatty acid synthesis through inhibition of ATP-citrate lyase and through activation of AMP-activated protein kinase. In this study, we tested the hypothesis that bempedoic acid would prevent diet-induced metabolic dysregulation, inflammation, and atherosclerosis. APPROACH AND RESULTS: Ldlr-/- mice were fed a high-fat, high-cholesterol diet (42% kcal fat, 0.2% cholesterol) supplemented with bempedoic acid at 0, 3, 10 and 30 mg/kg body weight/day. Treatment for 12 weeks dose-dependently attenuated diet-induced hypercholesterolemia, hypertriglyceridemia, hyperglycemia, hyperinsulinemia, fatty liver and obesity. Compared to high-fat, high-cholesterol alone, the addition of bempedoic acid decreased plasma triglyceride (up to 64%) and cholesterol (up to 50%) concentrations, and improved glucose tolerance. Adiposity was significantly reduced with treatment. In liver, bempedoic acid prevented cholesterol and triglyceride accumulation, which was associated with increased fatty acid oxidation and reduced fatty acid synthesis. Hepatic gene expression analysis revealed that treatment significantly increased expression of genes involved in fatty acid oxidation while suppressing inflammatory gene expression. In full-length aorta, bempedoic acid markedly suppressed cholesteryl ester accumulation, attenuated the expression of proinflammatory M1 genes and attenuated the iNos/Arg1 ratio. Treatment robustly attenuated atherosclerotic lesion development in the aortic sinus by 44%, with beneficial changes in morphology, characteristic of earlier-stage lesions. Bempedoic acid effectively prevents plasma and tissue lipid elevations and attenuates the onset of inflammation, leading to the prevention of atherosclerotic lesion development in a mouse model of metabolic dysregulation.
Highlights
Bempedoic acid prevented cholesterol and triglyceride accumulation, which was associated with increased fatty acid oxidation and reduced fatty acid synthesis
Hepatic gene expression analysis revealed that treatment significantly increased expression of genes involved in fatty acid oxidation while suppressing inflammatory gene expression
Large-scale clinical trials have consistently shown that lowering plasma low-density lipoprotein (LDL) cholesterol (C) concentrations reduces cardiovascular disease mortality.[1]
Summary
Bempedoic Acid Attenuates Weight Gain and Adipose Tissue Accumulation in HighFat, High-Cholesterol-Fed Ldlr−/− Mice Eight-week-old male Ldlr−/− mice were fed chow or a high-fat, high-cholesterol–containing diet (HFHC; 42% kcal fat, 0.2% cholesterol) supplemented with daily doses of 0, 3, 10, or 30 mg of BemA per kg body weight (mg/kg), for 12 weeks. The HFHC diet increased weight gain compared with chow-fed mice, which was partially prevented by treatment with 30 mg/ kg per day of BemA (Figure 1A). The 4.5-fold increase in epididymal fat pad weight induced by the HFHC diet was significantly attenuated (−29%) by BemA at 30 mg/kg per day (Figure 1B). Bempedoic Acid Improves Glucose Metabolism and Insulin Sensitivity The moderately elevated levels of blood glucose induced by the HFHC diet were significantly decreased by BemA at 30 mg/kg per day (−14%; Figure 1H). Glucose and insulin tolerance tests revealed a significant dosedependent improvement in glucose tolerance at 10 and 30 mg/kg per day, whereas insulin tolerance was unaffected by HFHC or BemA (Figure IC and ID in the online-only Data Supplement)
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