title: Fructose Mediated Non-Alcoholic Fatty Liver Is Attenuated by HO-1-SIRT1 Module in Murine Hepatocytes and Mice Fed a High Fructose Diet.
abstract: BACKGROUND
  Oxidative stress underlies the etiopathogenesis of nonalcoholic fatty liver disease (NAFLD), obesity and cardiovascular disease (CVD). Heme Oxygenase-1 (HO-1) is a potent endogenous antioxidant gene that plays a key role in decreasing oxidative stress. Sirtuin1 (SIRT1) belongs to the family of NAD-dependent de-acyetylases and is modulated by cellular redox.
  
  
  OBJECTIVE
  We hypothesize that fructose-induced obesity creates an inflammatory and oxidative environment conducive to the development of NAFLD and metabolic syndrome. The aim of this study is to determine whether HO-1 acts through SIRT1 to form a functional module within hepatocytes to attenuate steatohepatitis, hepatic fibrosis and cardiovascular dysfunction.
  
  
  RESULTS
  We examined the effect of fructose, on hepatocyte lipid accumulation and fibrosis in murine hepatocytes and in mice fed a high fructose diet in the presence and absence of CoPP, an inducer of HO-1, and SnMP, an inhibitor of HO activity. Fructose increased oxidative stress markers and decreased HO-1 and SIRT1 levels in hepatocytes (p<0.05). Further fructose supplementation increased FAS, PPARα, pAMPK and triglycerides levels; CoPP negated this increase. Concurrent treatment with CoPP and SIRT1 siRNA in hepatocytes increased FAS, PPARα, pAMPK and triglycerides levels suggesting that HO-1 is upstream of SIRT1 and suppression of SIRT1 attenuates the beneficial effects of HO-1. A high fructose diet increased insulin resistance, blood pressure, markers of oxidative stress and lipogenesis along with fibrotic markers in mice (p<0.05). Increased levels of HO-1 increased SIRT1 levels and ameliorated fructose-mediated lipid accumulation and fibrosis in liver along with decreasing vascular dysfunction (p<0.05 vs. fructose). These beneficial effects of CoPP were reversed by SnMP.
  
  
  CONCLUSIONS
  Taken together, our study demonstrates, for the first time, that HO-1 induction attenuates fructose-induced hepatic lipid deposition, prevents the development of hepatic fibrosis and abates NAFLD-associated vascular dysfunction; effects that are mediated by activation of SIRT1 gene expression.
authors.affiliation: Departments of Medicine and Surgery, Joan C. Edwards School of Medicine, Marshall University, Huntington, West Virginia, United States of America.
authors.forename: Komal
authors.initials: K
authors.lastname: Sodhi
authors.affiliation: Department of Physiology & Pharmacology, University of Toledo College of Medicine, Toledo, Ohio, United States of America.
authors.forename: Nitin
authors.initials: N
authors.lastname: Puri
authors.affiliation: Department of Clinical and Experimental Sciences, Division of Anatomy and Physiopathology, University of Brescia, Brescia, Italy.
authors.forename: Gaia
authors.initials: G
authors.lastname: Favero
authors.affiliation: Departments of Medicine and Surgery, Joan C. Edwards School of Medicine, Marshall University, Huntington, West Virginia, United States of America.
authors.forename: Sarah
authors.initials: S
authors.lastname: Stevens
authors.affiliation: Departments of Medicine and Surgery, Joan C. Edwards School of Medicine, Marshall University, Huntington, West Virginia, United States of America.
authors.forename: Charles
authors.initials: C
authors.lastname: Meadows
authors.affiliation: Departments of Medicine and Gastroenterology, New York Medical College, Valhalla, New York, United States of America.
authors.forename: Nader G
authors.initials: NG
authors.lastname: Abraham
authors.affiliation: Department of Clinical and Experimental Sciences, Division of Anatomy and Physiopathology, University of Brescia, Brescia, Italy.
authors.forename: Rita
authors.initials: R
authors.lastname: Rezzani
authors.affiliation: Departments of Medicine and Surgery, Joan C. Edwards School of Medicine, Marshall University, Huntington, West Virginia, United States of America.
authors.forename: Hayden
authors.initials: H
authors.lastname: Ansinelli
authors.affiliation: Departments of Medicine and Gastroenterology, New York Medical College, Valhalla, New York, United States of America.
authors.forename: Edward
authors.initials: E
authors.lastname: Lebovics
authors.affiliation: Departments of Medicine and Surgery, Joan C. Edwards School of Medicine, Marshall University, Huntington, West Virginia, United States of America.
authors.forename: Joseph I
authors.initials: JI
authors.lastname: Shapiro
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000818:Animals; D001794:Blood Pressure / Q000502:physiology; D002478:Cells, Cultured; D004032:Diet; D004789:Enzyme Activation; D005632:Fructose / Q000378:metabolism*; D051547:Heme Oxygenase-1 / Q000235:genetics / Q000378:metabolism*; D022781:Hepatocytes / Q000378:metabolism; D007333:Insulin Resistance / Q000502:physiology; D008099:Liver / Q000473:pathology; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D065626:Non-alcoholic Fatty Liver Disease / Q000235:genetics / Q000473:pathology*; D018384:Oxidative Stress; D047493:PPAR alpha / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering; D056564:Sirtuin 1 / Q000235:genetics / Q000378:metabolism*; D014280:Triglycerides / Q000097:blood; D019014:fas Receptor / Q000378:metabolism
chemical_list: C491899:Fas protein, mouse; D008565:Membrane Proteins; D047493:PPAR alpha; D034741:RNA, Small Interfering; D014280:Triglycerides; D019014:fas Receptor; D005632:Fructose; D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse; D055372:AMP-Activated Protein Kinases; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1