Prevention of Diet-Induced Metabolic Dysregulation, Inflammation, and Atherosclerosis inLdlr-/-Mice by Treatment With the ATP-Citrate Lyase Inhibitor Bempedoic Acid.
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 theiNos/Arg1ratio. 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.
From the Molecular Medicine Research Laboratory, Robarts Research Institute (J.P.S., A.C.B., B.G.S., D.E.T., C.G.S., J.Y.E., M.W.H.), Department of Biochemistry (J.P.S., A.C.B., M.W.H.), and Department of Medicine (D.E.T., C.G.S., J.Y.E., M.W.H.), The University of Western Ontario, London, Canada; and Esperion Therapeutics Inc, Ann Arbor, MI (S.L.P., R.S.N.).
Joshua P
JP
Samsoondar
From the Molecular Medicine Research Laboratory, Robarts Research Institute (J.P.S., A.C.B., B.G.S., D.E.T., C.G.S., J.Y.E., M.W.H.), Department of Biochemistry (J.P.S., A.C.B., M.W.H.), and Department of Medicine (D.E.T., C.G.S., J.Y.E., M.W.H.), The University of Western Ontario, London, Canada; and Esperion Therapeutics Inc, Ann Arbor, MI (S.L.P., R.S.N.).
Amy C
AC
Burke
From the Molecular Medicine Research Laboratory, Robarts Research Institute (J.P.S., A.C.B., B.G.S., D.E.T., C.G.S., J.Y.E., M.W.H.), Department of Biochemistry (J.P.S., A.C.B., M.W.H.), and Department of Medicine (D.E.T., C.G.S., J.Y.E., M.W.H.), The University of Western Ontario, London, Canada; and Esperion Therapeutics Inc, Ann Arbor, MI (S.L.P., R.S.N.).
Brian G
BG
Sutherland
From the Molecular Medicine Research Laboratory, Robarts Research Institute (J.P.S., A.C.B., B.G.S., D.E.T., C.G.S., J.Y.E., M.W.H.), Department of Biochemistry (J.P.S., A.C.B., M.W.H.), and Department of Medicine (D.E.T., C.G.S., J.Y.E., M.W.H.), The University of Western Ontario, London, Canada; and Esperion Therapeutics Inc, Ann Arbor, MI (S.L.P., R.S.N.).
Dawn E
DE
Telford
From the Molecular Medicine Research Laboratory, Robarts Research Institute (J.P.S., A.C.B., B.G.S., D.E.T., C.G.S., J.Y.E., M.W.H.), Department of Biochemistry (J.P.S., A.C.B., M.W.H.), and Department of Medicine (D.E.T., C.G.S., J.Y.E., M.W.H.), The University of Western Ontario, London, Canada; and Esperion Therapeutics Inc, Ann Arbor, MI (S.L.P., R.S.N.).
Cynthia G
CG
Sawyez
From the Molecular Medicine Research Laboratory, Robarts Research Institute (J.P.S., A.C.B., B.G.S., D.E.T., C.G.S., J.Y.E., M.W.H.), Department of Biochemistry (J.P.S., A.C.B., M.W.H.), and Department of Medicine (D.E.T., C.G.S., J.Y.E., M.W.H.), The University of Western Ontario, London, Canada; and Esperion Therapeutics Inc, Ann Arbor, MI (S.L.P., R.S.N.).
Jane Y
JY
Edwards
From the Molecular Medicine Research Laboratory, Robarts Research Institute (J.P.S., A.C.B., B.G.S., D.E.T., C.G.S., J.Y.E., M.W.H.), Department of Biochemistry (J.P.S., A.C.B., M.W.H.), and Department of Medicine (D.E.T., C.G.S., J.Y.E., M.W.H.), The University of Western Ontario, London, Canada; and Esperion Therapeutics Inc, Ann Arbor, MI (S.L.P., R.S.N.).
Stephen L
SL
Pinkosky
From the Molecular Medicine Research Laboratory, Robarts Research Institute (J.P.S., A.C.B., B.G.S., D.E.T., C.G.S., J.Y.E., M.W.H.), Department of Biochemistry (J.P.S., A.C.B., M.W.H.), and Department of Medicine (D.E.T., C.G.S., J.Y.E., M.W.H.), The University of Western Ontario, London, Canada; and Esperion Therapeutics Inc, Ann Arbor, MI (S.L.P., R.S.N.).
Roger S
RS
Newton
From the Molecular Medicine Research Laboratory, Robarts Research Institute (J.P.S., A.C.B., B.G.S., D.E.T., C.G.S., J.Y.E., M.W.H.), Department of Biochemistry (J.P.S., A.C.B., M.W.H.), and Department of Medicine (D.E.T., C.G.S., J.Y.E., M.W.H.), The University of Western Ontario, London, Canada; and Esperion Therapeutics Inc, Ann Arbor, MI (S.L.P., R.S.N.). mhuff@uwo.ca.
Murray W
MW
Huff
D001275:ATP Citrate (pro-S)-Lyase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D050197:Atherosclerosis / Q000097:blood / Q000201:enzymology / Q000235:genetics / Q000517:prevention & control*; D015415:Biomarkers / Q000097:blood; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism; D003998:Dicarboxylic Acids / Q000494:pharmacology*; D059305:Diet, High-Fat; D004195:Disease Models, Animal; D050171:Dyslipidemias / Q000097:blood / Q000201:enzymology / Q000235:genetics / Q000517:prevention & control*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005227:Fatty Acids / Q000494:pharmacology*; D005786:Gene Expression Regulation; D020022:Genetic Predisposition to Disease; D007249:Inflammation / Q000097:blood / Q000201:enzymology / Q000235:genetics / Q000517:prevention & control*; D018836:Inflammation Mediators / Q000097:blood; D007328:Insulin / Q000097:blood; D008055:Lipids / Q000097:blood; D008099:Liver / Q000187:drug effects* / Q000201:enzymology; D008297:Male; D018345:Mice, Knockout; D009765:Obesity / Q000097:blood / Q000201:enzymology / Q000235:genetics / Q000517:prevention & control*; D010641:Phenotype; D011973:Receptors, LDL / Q000172:deficiency* / Q000235:genetics; D013997:Time Factors
D015415:Biomarkers; D001786:Blood Glucose; D003998:Dicarboxylic Acids; D004791:Enzyme Inhibitors; D005227:Fatty Acids; D018836:Inflammation Mediators; D007328:Insulin; D008055:Lipids; D011973:Receptors, LDL; C581236:8-hydroxy-2,2,14,14-tetramethylpentadecanedioic acid; D001275:ATP Citrate (pro-S)-Lyase
adenosine triphosphate citrate lyase; atherosclerosis; inflammation; lipids