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]

• Published in: Journal of lipid research Vol. 54; no. 1; pp. 134 - 151
• Main Authors: Pinkosky, Stephen L., Filippov, Sergey, Srivastava, Rai Ajit K., Hanselman, Jeffrey C., Bradshaw, Cheryl D., Hurley, Timothy R., Cramer, Clay T., Spahr, Mark A., Brant, Ashley F., Houghton, Jacob L., Baker, Chris, Naples, Mark, Adeli, Khosrow, Newton, Roger S.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.01.2013; The American Society for Biochemistry and Molecular Biology; Elsevier
• Subjects: AMP-Activated Protein Kinases - metabolism; Animals; ATP Citrate (pro-S)-Lyase - antagonists & inhibitors; ATP Citrate (pro-S)-Lyase - metabolism; Biomarkers - blood; Biomarkers - metabolism; Calcium - metabolism; Carbohydrate Metabolism - drug effects; cardiovascular disease; cholesterol synthesis; Cricetinae; Dicarboxylic Acids - chemistry; Dicarboxylic Acids - pharmacology; Dicarboxylic Acids - therapeutic use; Diet - adverse effects; Dyslipidemias - blood; Dyslipidemias - drug therapy; Dyslipidemias - metabolism; Energy Metabolism - drug effects; Enzyme Activation - drug effects; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Enzyme Inhibitors - therapeutic use; fatty acid oxidation; fatty acid synthesis; Fatty Acids - biosynthesis; Fatty Acids - chemistry; Fatty Acids - pharmacology; Fatty Acids - therapeutic use; Female; Glucagon - metabolism; Glucose - biosynthesis; Hep G2 Cells; Humans; LDL-cholesterol; Lipid Metabolism - drug effects; Liver - cytology; Liver - drug effects; Liver - enzymology; Liver - metabolism; Male; metabolic syndrome; Mice; Molecular Targeted Therapy - methods; Obesity - blood; Obesity - drug therapy; Obesity - etiology; Obesity - metabolism; Protein-Serine-Threonine Kinases - metabolism; Rats; Signal Transduction - drug effects; Sterols - biosynthesis; metabolic syndrome; LDL-cholesterol; cardiovascular disease; fatty acid oxidation; fatty acid synthesis; cholesterol synthesis
• ISSN: 0022-2275; 1539-7262
• DOI: 10.1194/jlr.M030528

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.