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

被引:328
|
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
收藏
页数:13
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