Electronic Thesis and Dissertation Repository

Degree

Master of Science

Program

Biochemistry

Supervisor

Murray Huff

Abstract

Bempedoic acid (BA) is a novel LDL cholesterol-lowering compound. Preclinical studies revealed that BA inhibits hepatic cholesterol and fatty acid synthesis through inhibition of ATP-citrate lyase and activation of AMP-kinase. In the current study we tested the ability of BA to prevent diet-induced metabolic dysregulation, inflammation and atherosclerosis in Ldlr-/- mice fed a high-fat high-cholesterol diet (HFHC). BA supplementation to the HFHC diet at 3, 10 or 30 mg/kg/d significantly attenuated diet-induced hypercholesterolemia, hypertriglyceridemia, hyperglycemia, hyperinsulinemia, fatty liver and obesity over the 12- week study compared to HFHC alone. Livers of BA-treated mice displayed decreased fatty acid synthesis, and increased β-oxidation, AMP-kinase activation, and peroxisome proliferation. BA reduced hepatic and aortic inflammatory gene expression and MAPK signaling, aortic esterified cholesteryl, and atherosclerotic lesion development. This demonstrates that BA effectively improves hepatic lipid metabolism and reduces plasma and tissue lipids, markers of inflammation, and atherosclerosis in a mouse model of metabolic dysregulation.

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