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.

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

Grant support