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

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  • Stephen L. Pinkosky

    (Esperion Therapeutics, Inc.
    McMaster University, 1280 Main Street West)

  • 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
    McMaster University)

  • Narendra D. Lalwani

    (Esperion Therapeutics, Inc.)

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.

Suggested Citation

  • 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. Stein, 2016. "Liver-specific ATP-citrate lyase inhibition by bempedoic acid decreases LDL-C and attenuates atherosclerosis," Nature Communications, Nature, vol. 7(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:7:y:2016:i:1:d:10.1038_ncomms13457
    DOI: 10.1038/ncomms13457
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