• 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.
• Esperion Therapeutics, Inc., 3891 Ranchero Drive, Suite 150, Ann Arbor, Michigan 48108, USA.
• Nat Commun. 2016 Nov 28; 7: 13457.

AbstractDespite 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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