AMP-activated protein kinase and ATP-citrate lyase are two distinct molecular targets for ETC-1002, a novel small molecule regulator of lipid and carbohydrate metabolism[S]

Journal of Lipid Research

Rai Ajit K. Srivastava¹  Jeffrey C. Hanselman²  Cheryl D. Bradshaw³  Sergey Filippov³  Roger S. Newton⁴  Khosrow Adeli⁵  Timothy R. Hurley⁵  Clay T. Cramer⁵  Mark Naples⁵  Mark A. Spahr⁵  Jacob L. Houghton⁵  Ashley F. Brant⁵  Chris Baker⁵  Stephen L. Pinkosky⁶ 

[1] Esperion Therapeutics, Inc., Plymouth, MI;To whom correspondence should be addressed. e-mail: [e-mail] (S.L.P);[e-mail] (R.S.N.).;Cellular Biotechnology Training Program, University of Michigan, Ann Arbor, MI;Esperion Therapeutics, Inc., Plymouth, MI;To whom correspondence should be addressed. e-mail: [e-mail] (S.L.P);

关键词: fatty acid synthesis;    cholesterol synthesis;    fatty acid oxidation;    LDL-cholesterol;    cardiovascular disease;    metabolic syndrome;   

DOI  :  

来源: DOAJ

【 摘 要 】

ETC-1002 (8-hydroxy-2,2,14,14-tetramethylpentadecanedioic acid) is a novel investigational drug being developed for the treatment of dyslipidemia and other cardio-metabolic risk factors. The hypolipidemic, anti-atherosclerotic, anti-obesity, and glucose-lowering properties of ETC-1002, characterized in preclinical disease models, are believed to be due to dual inhibition of sterol and fatty acid synthesis and enhanced mitochondrial long-chain fatty acid β-oxidation. However, the molecular mechanism(s) mediating these activities remained undefined. Studies described here show that ETC-1002 free acid activates AMP-activated protein kinase in a Ca2+/calmodulin-dependent kinase β-independent and liver kinase β 1-dependent manner, without detectable changes in adenylate energy charge. Furthermore, ETC-1002 is shown to rapidly form a CoA thioester in liver, which directly inhibits ATP-citrate lyase. These distinct molecular mechanisms are complementary in their beneficial effects on lipid and carbohydrate metabolism in vitro and in vivo. Consistent with these mechanisms, ETC-1002 treatment reduced circulating proatherogenic lipoproteins, hepatic lipids, and body weight in a hamster model of hyperlipidemia, and it reduced body weight and improved glycemic control in a mouse model of diet-induced obesity. ETC-1002 offers promise as a novel therapeutic approach to improve multiple risk factors associated with metabolic syndrome and benefit patients with cardiovascular disease.

【 授权许可】

Unknown