Abstract 14653: Prevention of Diet-induced Metabolic Dysregulation, Inflammation and Atherosclerosis in Ldlr-/- Mice by Treatment With the ACL Inhibitor ETC-1002
ETC-1002 (8-hydroxy-2,2,14,14-tetramethylpentadecanedioic acid) is a novel LDL cholesterol-lowering compound. Preclinical studies revealed that ETC-1002 targets the liver where its metabolite, ETC-1002-CoA, inhibits the synthesis of sterols and fatty acids. The primary mechanism of action is through inhibition of hepatic ATP-citrate lyase (ACL). In the current study we tested the ability of ETC-1002 to prevent diet-induced metabolic dysregulation, inflammation and atherosclerosis in LDL receptor deficient (Ldlr-/-) mice. Ldlr-/- mice fed a high-fat high-cholesterol diet (42% kcal fat; 0.2% cholesterol; HFHC) developed hypercholesterolemia, hypertriglyceridemia, hyperglycemia, hyperinsulinemia, fatty liver and obesity over the 12 week study. ETC-1002 supplementation to the HFHC diet at 3, 10 and 30 mg/kg/d significantly attenuated these metabolic abnormalities in a dose-dependent manner. ETC-1002 + HFHC attenuated plasma triglyceride (up to 64%) and plasma cholesterol concentrations (up to 50%), and improved glucose homeostasis compared to HFHC alone as determined by glucose tolerance tests. Adiposity was attenuated up to 48% with treatment. In liver, ETC-1002 dose dependently prevented cholesterol and triglyceride accumulation up to 75% and 90%, respectively. Hepatic gene expression analysis revealed that treatment significantly reduced the expression of the inflammatory genes Tnfa, Il1b, Ccl3 and Nos2 as well as increased the expression of genes involved in mitochondrial (Cpt1a, 1.3-fold) and peroxisomal (Acox1, 4.1-fold) fatty acid beta-oxidation. ETC-1002 reduced aortic cholesterol ester content by up to 63% and robustly attenuated atherosclerotic lesion development in the aortic sinus by 48%. These studies demonstrate that ETC-1002 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.