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

• Published in: Nature communications 2016-11, Vol.7 (1), p.13457-13457, Article 13457
• Main Authors: Pinkosky, Stephen L., Newton, Roger S., Day, Emily A., Ford, Rebecca J., Lhotak, Sarka, Austin, Richard C., Birch, Carolyn M., Smith, Brennan K., Filippov, Sergey, Groot, Pieter H.E., Steinberg, Gregory R., Lalwani, Narendra D.
• Format: Article
• Language: English
• Subjects: 13; 38; 38/1; 38/109; 38/39; 38/77; 38/89; 38/90; 59; 631/154/555; 64; 692/699/75/593/2100; 82; 96; 96/1; 96/95; Adenylate Kinase - metabolism; Animals; Atherosclerosis; Atherosclerosis - drug therapy; Atherosclerosis - enzymology; Atherosclerosis - pathology; ATP Citrate (pro-S)-Lyase - antagonists & inhibitors; ATP Citrate (pro-S)-Lyase - metabolism; Biosynthesis; Cholesterol; Cholesterol, LDL - metabolism; Dicarboxylic Acids - chemistry; Dicarboxylic Acids - metabolism; Dicarboxylic Acids - pharmacology; Disease Progression; Drug dosages; Enzyme Activation - drug effects; Enzyme Inhibitors - pharmacology; Enzyme Inhibitors - therapeutic use; Enzymes; Fatty acids; Fatty Acids - chemistry; Fatty Acids - metabolism; Fatty Acids - pharmacology; Hepatocytes - drug effects; Hepatocytes - metabolism; Humanities and Social Sciences; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors - adverse effects; Hydroxymethylglutaryl-CoA Reductase Inhibitors - therapeutic use; Kinases; Lipid Metabolism - drug effects; Lipids; Lipoproteins; Liver - enzymology; Metabolism; Mice, Inbred C57BL; Mice, Knockout; Models, Biological; multidisciplinary; Musculoskeletal system; Organ Specificity; Receptors, LDL - metabolism; Science; Science (multidisciplinary); Statins; Up-Regulation - drug effects
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/ncomms13457

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. Statins are lipid-lowering drugs that prevent cardiovascular disease but tolerability is limited by severe side effects in muscles. Here the authors elucidate a liver-specific activation mechanism for bempedoic acid, a novel cholesterol-lowering drug, and show how it effectively reduces LDL-C and atherosclerotic burden in mice, but does not cause myotoxicty.