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

被引：349

作者：

Pinkosky, Stephen L. ^{[1
,2
]}

Newton, Roger S. ^{[1
]}

Day, Emily A. ^{[2
]}

Ford, Rebecca J. ^{[2
]}

Lhotak, Sarka ^{[3
]}

Austin, Richard C. ^{[3
]}

Birch, Carolyn M. ^{[1
]}

Smith, Brennan K. ^{[2
]}

Filippov, Sergey ^{[1
]}

Groot, Pieter H. E. ^{[1
]}

Steinberg, Gregory R. ^{[2
,4
]}

Lalwani, Narendra D. ^{[1
]}

机构：

[1] Esper Therapeut Inc, 3891 Ranchero Dr,Suite 150, Ann Arbor, MI 48108 USA

[2] McMaster Univ, Div Endocrinol & Metab, Dept Med, 1280 Main St West, Hamilton, ON L8S 4K1, Canada

[3] McMaster Univ, St Josephs Healthcare Hamilton, Dept Med, 50 Charlton Ave East, Hamilton, ON L8N 4A6, Canada

[4] McMaster Univ, Dept Biochem & Biomed Sci, 1280 Main St West, Hamilton, ON L8S 4K1, Canada

来源：

NATURE COMMUNICATIONS | 2016年 / 7卷

基金：

加拿大健康研究院;

关键词：

ACTIVATED PROTEIN-KINASE; LOW-DENSITY-LIPOPROTEIN; ACYL-COA SYNTHETASE; FATTY-ACID; STATIN THERAPY; HYPOLIPIDEMIC INTERVENTION; REDUCING LIPIDS; MUSCLE TOXICITY; CITRIC-ACID; TRIACSIN-C;

D O I：

10.1038/ncomms13457

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页数：13

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