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 () and Narendra D. Lalwani
Additional contact information
Stephen L. Pinkosky: Esperion Therapeutics, Inc.
Roger S. Newton: Esperion Therapeutics, Inc.
Emily A. Day: McMaster University, 1280 Main Street West
Rebecca J. Ford: McMaster University, 1280 Main Street West
Sarka Lhotak: McMaster University, St Joseph’s Healthcare Hamilton
Richard C. Austin: McMaster University, St Joseph’s Healthcare Hamilton
Carolyn M. Birch: Esperion Therapeutics, Inc.
Brennan K. Smith: McMaster University, 1280 Main Street West
Sergey Filippov: Esperion Therapeutics, Inc.
Pieter H.E. Groot: Esperion Therapeutics, Inc.
Gregory R. Steinberg: McMaster University, 1280 Main Street West
Narendra D. Lalwani: Esperion Therapeutics, Inc.

Nature Communications, 2016, vol. 7, issue 1, 1-13

Abstract: 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.

Date: 2016
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DOI: 10.1038/ncomms13457

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