title: Liver-specific ATP-citrate lyase inhibition by bempedoic acid decreases LDL-C and attenuates atherosclerosis.
abstract: Despite widespread use of statins to reduce low-density lipoprotein cholesterol (LDL-C) and associated atherosclerotic cardiovascular risk, many patients do not achieve sufficient LDL-C lowering due to muscle-related side effects, indicating novel treatment strategies are required. Bempedoic acid (ETC-1002) is a small molecule intended to lower LDL-C in hypercholesterolemic patients, and has been previously shown to modulate both ATP-citrate lyase (ACL) and AMP-activated protein kinase (AMPK) activity in rodents. However, its mechanism for LDL-C lowering, efficacy in models of atherosclerosis and relevance in humans are unknown. Here we show that ETC-1002 is a prodrug that requires activation by very long-chain acyl-CoA synthetase-1 (ACSVL1) to modulate both targets, and that inhibition of ACL leads to LDL receptor upregulation, decreased LDL-C and attenuation of atherosclerosis, independently of AMPK. Furthermore, we demonstrate that the absence of ACSVL1 in skeletal muscle provides a mechanistic basis for ETC-1002 to potentially avoid the myotoxicity associated with statin therapy.
authors.affiliation: Esperion Therapeutics, Inc., 3891 Ranchero Drive, Suite 150, Ann Arbor, Michigan 48108, USA.|Division of Endocrinology and Metabolism, Department of Medicine, McMaster University, 1280 Main Street West, Hamilton, Ontario, Canada L8S 4K1.
authors.forename: Stephen L
authors.initials: SL
authors.lastname: Pinkosky
authors.affiliation: Esperion Therapeutics, Inc., 3891 Ranchero Drive, Suite 150, Ann Arbor, Michigan 48108, USA.
authors.forename: Roger S
authors.initials: RS
authors.lastname: Newton
authors.affiliation: Division of Endocrinology and Metabolism, Department of Medicine, McMaster University, 1280 Main Street West, Hamilton, Ontario, Canada L8S 4K1.
authors.forename: Emily A
authors.initials: EA
authors.lastname: Day
authors.affiliation: Division of Endocrinology and Metabolism, Department of Medicine, McMaster University, 1280 Main Street West, Hamilton, Ontario, Canada L8S 4K1.
authors.forename: Rebecca J
authors.initials: RJ
authors.lastname: Ford
authors.affiliation: Department of Medicine, McMaster University, St Joseph's Healthcare Hamilton, 50 Charlton Avenue East, Hamilton, Ontario, Canada L8N 4A6.
authors.forename: Sarka
authors.initials: S
authors.lastname: Lhotak
authors.affiliation: Department of Medicine, McMaster University, St Joseph's Healthcare Hamilton, 50 Charlton Avenue East, Hamilton, Ontario, Canada L8N 4A6.
authors.forename: Richard C
authors.initials: RC
authors.lastname: Austin
authors.affiliation: Esperion Therapeutics, Inc., 3891 Ranchero Drive, Suite 150, Ann Arbor, Michigan 48108, USA.
authors.forename: Carolyn M
authors.initials: CM
authors.lastname: Birch
authors.affiliation: Division of Endocrinology and Metabolism, Department of Medicine, McMaster University, 1280 Main Street West, Hamilton, Ontario, Canada L8S 4K1.
authors.forename: Brennan K
authors.initials: BK
authors.lastname: Smith
authors.affiliation: Esperion Therapeutics, Inc., 3891 Ranchero Drive, Suite 150, Ann Arbor, Michigan 48108, USA.
authors.forename: Sergey
authors.initials: S
authors.lastname: Filippov
authors.affiliation: Esperion Therapeutics, Inc., 3891 Ranchero Drive, Suite 150, Ann Arbor, Michigan 48108, USA.
authors.forename: Pieter H E
authors.initials: PHE
authors.lastname: Groot
authors.affiliation: Division of Endocrinology and Metabolism, Department of Medicine, McMaster University, 1280 Main Street West, Hamilton, Ontario, Canada L8S 4K1.|Department of Biochemistry and Biomedical Sciences, McMaster University, 1280 Main Street West, Hamilton, Ontario, Canada L8S 4K1.
authors.forename: Gregory R
authors.initials: GR
authors.lastname: Steinberg
authors.affiliation: Esperion Therapeutics, Inc., 3891 Ranchero Drive, Suite 150, Ann Arbor, Michigan 48108, USA.
authors.forename: Narendra D
authors.initials: ND
authors.lastname: Lalwani
mesh_terms: D001275:ATP Citrate (pro-S)-Lyase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000263:Adenylate Kinase / Q000378:metabolism; D000818:Animals; D050197:Atherosclerosis / Q000188:drug therapy* / Q000201:enzymology* / Q000473:pathology; D008078:Cholesterol, LDL / Q000378:metabolism*; D003998:Dicarboxylic Acids / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D018450:Disease Progression; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D005227:Fatty Acids / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000009:adverse effects / Q000627:therapeutic use; D050356:Lipid Metabolism / Q000187:drug effects; D008099:Liver / Q000201:enzymology*; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008954:Models, Biological; D009928:Organ Specificity; D011973:Receptors, LDL / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D008078:Cholesterol, LDL; D003998:Dicarboxylic Acids; D004791:Enzyme Inhibitors; D005227:Fatty Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011973:Receptors, LDL; C581236:8-hydroxy-2,2,14,14-tetramethylpentadecanedioic acid; D001275:ATP Citrate (pro-S)-Lyase; D000263:Adenylate Kinase