Liver-specific ATP-citrate lyase inhibition by bempedoic acid decreases LDL-C and attenuates atherosclerosis

Stephen L Pinkosky; Roger S Newton; Emily A Day; Rebecca J Ford; Sarka Lhotak; Richard C Austin; Carolyn M Birch; Brennan K Smith; Sergey Filippov; Pieter H E Groot; Gregory R Steinberg; Narendra D Lalwani

doi:10.1038/ncomms13457

Liver-specific ATP-citrate lyase inhibition by bempedoic acid decreases LDL-C and attenuates atherosclerosis

Nat Commun. 2016 Nov 28:7:13457. doi: 10.1038/ncomms13457.

Authors

Affiliations

¹ Esperion Therapeutics, Inc., 3891 Ranchero Drive, Suite 150, Ann Arbor, Michigan 48108, USA.
² Division of Endocrinology and Metabolism, Department of Medicine, McMaster University, 1280 Main Street West, Hamilton, Ontario, Canada L8S 4K1.
³ Department of Medicine, McMaster University, St Joseph's Healthcare Hamilton, 50 Charlton Avenue East, Hamilton, Ontario, Canada L8N 4A6.
⁴ Department of Biochemistry and Biomedical Sciences, McMaster University, 1280 Main Street West, Hamilton, Ontario, Canada L8S 4K1.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

ATP Citrate (pro-S)-Lyase / antagonists & inhibitors*
ATP Citrate (pro-S)-Lyase / metabolism
Adenylate Kinase / metabolism
Animals
Atherosclerosis / drug therapy*
Atherosclerosis / enzymology*
Atherosclerosis / pathology
Cholesterol, LDL / metabolism*
Dicarboxylic Acids / chemistry
Dicarboxylic Acids / metabolism
Dicarboxylic Acids / pharmacology*
Disease Progression
Enzyme Activation / drug effects
Enzyme Inhibitors / pharmacology*
Enzyme Inhibitors / therapeutic use
Fatty Acids / chemistry
Fatty Acids / metabolism
Fatty Acids / pharmacology*
Hepatocytes / drug effects
Hepatocytes / metabolism
Humans
Hydroxymethylglutaryl-CoA Reductase Inhibitors / adverse effects
Hydroxymethylglutaryl-CoA Reductase Inhibitors / therapeutic use
Lipid Metabolism / drug effects
Liver / enzymology*
Mice, Inbred C57BL
Mice, Knockout
Models, Biological
Organ Specificity
Receptors, LDL / metabolism
Up-Regulation / drug effects

Substances

Cholesterol, LDL
Dicarboxylic Acids
Enzyme Inhibitors
Fatty Acids
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Receptors, LDL
8-hydroxy-2,2,14,14-tetramethylpentadecanedioic acid
ATP Citrate (pro-S)-Lyase
Adenylate Kinase

Grants and funding

CIHR/Canada