title: Human resistin stimulates hepatic overproduction of atherogenic ApoB-containing lipoprotein particles by enhancing ApoB stability and impairing intracellular insulin signaling.
abstract: BACKGROUND
  Obese individuals are at high risk for developing atherosclerosis primarily attributable to elevated plasma concentrations of apolipoprotein (apo)B-containing particles, including very-low-density lipoprotein (VLDL). Plasma levels of the adipose tissue adipokine resistin are increased in human obesity, and resistin expression is positively correlated with coronary atherosclerosis and VLDL levels.
  
  
  OBJECTIVE
  We sought to determine for the first time whether resistin directly stimulates human hepatocyte production of apoB-containing particles and to elucidate the mechanisms responsible.
  
  
  RESULTS
  Treatment of human hepatocytes with resistin at levels observed in human obesity stimulated apoB secretion up to 10-fold, because of increased microsomal triglyceride transfer protein (MTP) activity and decreased expression/phosphorylation of proteins in the insulin signaling pathways (insulin receptor substrate-2, Akt, and extracellular signal-regulated kinase). Resistin also increased hepatocyte lipid content by stimulating de novo lipogenesis via the SREBP1 and SREBP2 pathways. Furthermore, obese serum with elevated resistin levels induced greater hepatocyte stimulation of apoB secretion than lean human serum, an effect that was ameliorated by antibody immunoprecipitation removal of serum resistin.
  
  
  CONCLUSIONS
  Resistin has a direct deleterious impact on human hepatic lipid and lipoprotein regulation. Resistin greatly increased hepatocyte VLDL apoB and lipid secretion because of MTP activation and induction of hepatocyte insulin resistance. Conversely, antibody removal of serum resistin ameliorated human serum stimulation of apoB secretion. Increased hepatic cellular lipids mediated by resistin reflects the fatty liver/steatosis observed with elevated resistin in humans. Thus, human resistin is a novel therapeutic target for mitigating common hepatic pathophysiological processes associated with human obesity, dyslipidemia and atherosclerosis.
authors.affiliation: Department of Medicine, Thrombosis and Atherosclerosis Research Institute, David Braley Cardiac, Vascular, and Stroke Research Institute, Hamilton General Hospital, Hamilton, ON, Canada.
authors.forename: Justina
authors.initials: J
authors.lastname: Costandi
authors.forename: Michelle
authors.initials: M
authors.lastname: Melone
authors.forename: Alex
authors.initials: A
authors.lastname: Zhao
authors.forename: Shirya
authors.initials: S
authors.lastname: Rashid
mesh_terms: D000818:Animals; D001055:Apolipoproteins B / Q000235:genetics / Q000378:metabolism*; D002352:Carrier Proteins / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004355:Drug Stability; D005234:Fatty Liver / Q000209:etiology; D056945:Hep G2 Cells / Q000187:drug effects / Q000378:metabolism; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D007333:Insulin Resistance; D007425:Intracellular Membranes / Q000378:metabolism*; D050356:Lipid Metabolism / Q000187:drug effects; D008079:Lipoproteins, VLDL / Q000378:metabolism*; D008099:Liver / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D051379:Mice; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D052243:Resistin / Q000008:administration & dosage*; D015398:Signal Transduction / Q000187:drug effects*; D051780:Sterol Regulatory Element Binding Protein 1 / Q000378:metabolism; D051782:Sterol Regulatory Element Binding Protein 2 / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D001055:Apolipoproteins B; D002352:Carrier Proteins; D007328:Insulin; D008079:Lipoproteins, VLDL; C499624:RETN protein, human; D012333:RNA, Messenger; D052243:Resistin; C497387:SREBF1 protein, human; C497390:SREBF2 protein, human; D051780:Sterol Regulatory Element Binding Protein 1; D051782:Sterol Regulatory Element Binding Protein 2; C106092:microsomal triglyceride transfer protein