title: Discovery of a new role of human resistin in hepatocyte low-density lipoprotein receptor suppression mediated in part by proprotein convertase subtilisin/kexin type 9.
abstract: OBJECTIVE
  In this study, our goal was to determine if human resistin plays a role in regulating the uptake of atherogenic low-density lipoproteins in human hepatocytes.
  
  
  BACKGROUND
  Serum levels of resistin, an adipose tissue-derived adipokine, are increased in human obesity and are positively correlated with atherosclerotic cardiovascular diseases. However, the function of resistin in humans is enigmatic.
  
  
  METHODS
  Human hepatocytes (HepG2 and primary) were treated (24 h) with the following: 1) purified human resistin at various concentrations, with and without lovastatin; and 2) obese human serum with elevated resistin levels or serum from which resistin was removed via antibody-immunoprecipitation. The effect of the treatments on cellular low-density lipoprotein receptor (LDLR) and proprotein convertase subtilisin/kexin type 9 (PCSK9) messenger ribonucleic acid and protein levels were determined by using real-time polymerase chain reaction and Western blotting, respectively.
  
  
  RESULTS
  Resistin, at physiological levels observed in human obesity, down-regulated hepatocyte LDLR expression substantially (by 40%). A key mechanism by which human resistin inhibited LDLR levels was by increased cellular expression of the recently identified protease, PCSK9, which enhances intracellular LDLR lysosomal degradation. The quantitatively important role of human resistin in LDLR expression was demonstrated by antibody-immunoprecipitation removal of resistin in human serum, which decreased serum stimulation of hepatocyte LDLRs markedly (by 80%). Furthermore, resistin diminished statin-mediated up-regulation of the LDLR by 60%, implicating resistin in the relative ineffectiveness of statins in selective target populations.
  
  
  CONCLUSIONS
  These results reveal for the first time that resistin is a highly attractive therapeutic target in ameliorating elevated serum low-density lipoprotein and, thereby, atherosclerotic cardiovascular diseases in obese humans.
authors.affiliation: Department of Medicine, Thrombosis and Atherosclerosis Research Institute, David Braley Cardiac, Vascular and Stroke Research Institute, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Michelle
authors.initials: M
authors.lastname: Melone
authors.forename: Larissa
authors.initials: L
authors.lastname: Wilsie
authors.forename: Oksana
authors.initials: O
authors.lastname: Palyha
authors.forename: Alison
authors.initials: A
authors.lastname: Strack
authors.forename: Shirya
authors.initials: S
authors.lastname: Rashid
mesh_terms: D004305:Dose-Response Relationship, Drug; D050171:Dyslipidemias / Q000378:metabolism*; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000378:metabolism*; D006801:Humans; D047468:Immunoprecipitation; D008148:Lovastatin / Q000494:pharmacology; D008954:Models, Biological; D009765:Obesity / Q000097:blood; D043484:Proprotein Convertases / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction / Q000379:methods; D011973:Receptors, LDL / Q000037:antagonists & inhibitors* / Q000378:metabolism; D052243:Resistin / Q000096:biosynthesis*; D020860:Subtilisin / Q000096:biosynthesis*
chemical_list: C499624:RETN protein, human; D012333:RNA, Messenger; D011973:Receptors, LDL; D052243:Resistin; D008148:Lovastatin; D043484:Proprotein Convertases; D020860:Subtilisin