Liver-specific ATP-citrate Lyase Inhibition by Bempedoic Acid Decreases LDL-C and Attenuates Atherosclerosis

Overview

Journal Nat Commun

Specialty Biology

Date 2016 Nov 29

PMID 27892461

Citations 129

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

Affiliations

Soon will be listed here.

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.

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