title: ETC-1002 regulates immune response, leukocyte homing, and adipose tissue inflammation via LKB1-dependent activation of macrophage AMPK.
abstract: ETC-1002 is an investigational drug currently in Phase 2 development for treatment of dyslipidemia and other cardiometabolic risk factors. In dyslipidemic subjects, ETC-1002 not only reduces plasma LDL cholesterol but also significantly attenuates levels of hsCRP, a clinical biomarker of inflammation. Anti-inflammatory properties of ETC-1002 were further investigated in primary human monocyte-derived macrophages and in in vivo models of inflammation. In cells treated with ETC-1002, increased levels of AMP-activated protein kinase (AMPK) phosphorylation coincided with reduced activity of MAP kinases and decreased production of proinflammatory cytokines and chemokines. AMPK phosphorylation and inhibitory effects of ETC-1002 on soluble mediators of inflammation were significantly abrogated by siRNA-mediated silencing of macrophage liver kinase B1 (LKB1), indicating that ETC-1002 activates AMPK and exerts its anti-inflammatory effects via an LKB1-dependent mechanism. In vivo, ETC-1002 suppressed thioglycollate-induced homing of leukocytes into mouse peritoneal cavity. Similarly, in a mouse model of diet-induced obesity, ETC-1002 restored adipose AMPK activity, reduced JNK phosphorylation, and diminished expression of macrophage-specific marker 4F/80. These data were consistent with decreased epididymal fat-pad mass and interleukin (IL)-6 release by inflamed adipose tissue. Thus, ETC-1002 may provide further clinical benefits for patients with cardiometabolic risk factors by reducing systemic inflammation linked to insulin resistance and vascular complications of metabolic syndrome.
authors.affiliation: Esperion Therapeutics Inc., Plymouth, MI 48170.
authors.forename: Sergey
authors.initials: S
authors.lastname: Filippov
authors.affiliation: Esperion Therapeutics Inc., Plymouth, MI 48170.
authors.forename: Stephen L
authors.initials: SL
authors.lastname: Pinkosky
authors.affiliation: Esperion Therapeutics Inc., Plymouth, MI 48170.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Lister
authors.affiliation: Esperion Therapeutics Inc., Plymouth, MI 48170.
authors.forename: Catherine
authors.initials: C
authors.lastname: Pawloski
authors.affiliation: Esperion Therapeutics Inc., Plymouth, MI 48170.
authors.forename: Jeffrey C
authors.initials: JC
authors.lastname: Hanselman
authors.affiliation: Esperion Therapeutics Inc., Plymouth, MI 48170.
authors.forename: Clay T
authors.initials: CT
authors.lastname: Cramer
authors.affiliation: Esperion Therapeutics Inc., Plymouth, MI 48170.
authors.forename: Rai Ajit K
authors.initials: RAK
authors.lastname: Srivastava
authors.affiliation: Esperion Therapeutics Inc., Plymouth, MI 48170.
authors.forename: Timothy R
authors.initials: TR
authors.lastname: Hurley
authors.affiliation: Esperion Therapeutics Inc., Plymouth, MI 48170.
authors.forename: Cheryl D
authors.initials: CD
authors.lastname: Bradshaw
authors.affiliation: Esperion Therapeutics Inc., Plymouth, MI 48170.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Spahr
authors.affiliation: Esperion Therapeutics Inc., Plymouth, MI 48170. Electronic address: sfilippov@esperion.com.
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*; D000273:Adipose Tissue / Q000166:cytology / Q000187:drug effects* / Q000276:immunology; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D003998:Dicarboxylic Acids / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005227:Fatty Acids / Q000494:pharmacology*; D006801:Humans; D007249:Inflammation; D007962:Leukocytes / Q000166:cytology / Q000187:drug effects* / Q000276:immunology; D008264:Macrophages / Q000187:drug effects / Q000201:enzymology*; D008297:Male; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D003998:Dicarboxylic Acids; D005227:Fatty Acids; C581236:8-hydroxy-2,2,14,14-tetramethylpentadecanedioic acid; D017346:Protein Serine-Threonine Kinases; C488755:Stk11 protein, rat; D000091162:AMP-Activated Protein Kinase Kinases; D055372:AMP-Activated Protein Kinases
keywords: AMP-activated protein kinase; adipose tissue; cardiometabolic risk factors; cytokines; drug therapy; hypolipidemic drugs; liver kinase B1; macrophages/monocytes; mitogen-activated protein kinases