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

• DOI: 10.1038/ncomms13457
• Publication Date: 2016-11-28T10:52:05Z
• Authors: 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
• Keywords: ATP citrate lyase

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 muscle-related side effects, indicating novel treatment strategies are required. Bempedoic acid (ETC-1002) is a small molecule intended lower in hypercholesterolemic patients, has been previously shown modulate both ATP-citrate lyase (ACL) AMP-activated protein kinase (AMPK) activity rodents. However, its mechanism for lowering, efficacy models atherosclerosis relevance humans unknown. Here we show that ETC-1002 prodrug requires activation by very long-chain acyl-CoA synthetase-1 (ACSVL1) targets, inhibition ACL leads LDL receptor upregulation, decreased attenuation atherosclerosis, independently AMPK. Furthermore, demonstrate the absence ACSVL1 skeletal muscle provides mechanistic basis potentially avoid myotoxicity with statin therapy.