ETC-1002 regulates immune response, leukocyte homing, and adipose tissue inflammation via LKB1-dependent activation of macrophage AMPK

J Lipid Res. 2013 Aug;54(8):2095-2108. doi: 10.1194/jlr.M035212. Epub 2013 May 24.

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.

Keywords: AMP-activated protein kinase; adipose tissue; cardiometabolic risk factors; cytokines; drug therapy; hypolipidemic drugs; liver kinase B1; macrophages/monocytes; mitogen-activated protein kinases.

MeSH terms

  • AMP-Activated Protein Kinases / metabolism*
  • Adipose Tissue / cytology
  • Adipose Tissue / drug effects*
  • Adipose Tissue / immunology
  • Animals
  • Anti-Inflammatory Agents, Non-Steroidal / pharmacology*
  • Dicarboxylic Acids / pharmacology*
  • Dose-Response Relationship, Drug
  • Fatty Acids / pharmacology*
  • Humans
  • Inflammation
  • Leukocytes / cytology
  • Leukocytes / drug effects*
  • Leukocytes / immunology
  • Macrophages / drug effects
  • Macrophages / enzymology*
  • Male
  • Phosphorylation
  • Protein-Serine-Threonine Kinases / metabolism*
  • Rats
  • Rats, Sprague-Dawley
  • Structure-Activity Relationship

Substances

  • Anti-Inflammatory Agents, Non-Steroidal
  • Dicarboxylic Acids
  • Fatty Acids
  • 8-hydroxy-2,2,14,14-tetramethylpentadecanedioic acid
  • Protein-Serine-Threonine Kinases
  • Stk11 protein, rat
  • AMP-Activated Protein Kinases