title: 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.
abstract: 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 Ca(2+)/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.
authors.affiliation: Esperion Therapeutics, Inc., Plymouth, MI, USA. spinkosky@esperion.com
authors.forename: Stephen L
authors.initials: SL
authors.lastname: Pinkosky
authors.forename: Sergey
authors.initials: S
authors.lastname: Filippov
authors.forename: Rai Ajit K
authors.initials: RA
authors.lastname: Srivastava
authors.forename: Jeffrey C
authors.initials: JC
authors.lastname: Hanselman
authors.forename: Cheryl D
authors.initials: CD
authors.lastname: Bradshaw
authors.forename: Timothy R
authors.initials: TR
authors.lastname: Hurley
authors.forename: Clay T
authors.initials: CT
authors.lastname: Cramer
authors.forename: Mark A
authors.initials: MA
authors.lastname: Spahr
authors.forename: Ashley F
authors.initials: AF
authors.lastname: Brant
authors.forename: Jacob L
authors.initials: JL
authors.lastname: Houghton
authors.forename: Chris
authors.initials: C
authors.lastname: Baker
authors.forename: Mark
authors.initials: M
authors.lastname: Naples
authors.forename: Khosrow
authors.initials: K
authors.lastname: Adeli
authors.forename: Roger S
authors.initials: RS
authors.lastname: Newton
mesh_terms: D000091162:AMP-Activated Protein Kinase Kinases; D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D001275:ATP Citrate (pro-S)-Lyase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000818:Animals; D015415:Biomarkers / Q000097:blood / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D050260:Carbohydrate Metabolism / Q000187:drug effects*; D006224:Cricetinae; D003998:Dicarboxylic Acids / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D004032:Diet / Q000009:adverse effects; D050171:Dyslipidemias / Q000097:blood / Q000188:drug therapy / Q000378:metabolism; D004734:Energy Metabolism / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D005227:Fatty Acids / Q000096:biosynthesis / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D005260:Female; D005934:Glucagon / Q000378:metabolism; D005947:Glucose / Q000096:biosynthesis; D056945:Hep G2 Cells; D006801:Humans; D050356:Lipid Metabolism / Q000187:drug effects*; D008099:Liver / Q000166:cytology / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D008297:Male; D051379:Mice; D058990:Molecular Targeted Therapy / Q000379:methods*; D009765:Obesity / Q000097:blood / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects; D013261:Sterols / Q000096:biosynthesis
chemical_list: D015415:Biomarkers; D003998:Dicarboxylic Acids; D004791:Enzyme Inhibitors; D005227:Fatty Acids; D013261:Sterols; C581236:8-hydroxy-2,2,14,14-tetramethylpentadecanedioic acid; D005934:Glucagon; C117025:pentadecanoic acid; D001275:ATP Citrate (pro-S)-Lyase; D017346:Protein Serine-Threonine Kinases; C109790:STK11 protein, human; D000091162:AMP-Activated Protein Kinase Kinases; D055372:AMP-Activated Protein Kinases; D005947:Glucose; D002118:Calcium