title: Increased HO-1 levels ameliorate fatty liver development through a reduction of heme and recruitment of FGF21.
abstract: OBJECTIVE
  Obese leptin deficient (ob/ob) mice are a model of adiposity that displays increased levels of fat, glucose, and liver lipids. Our hypothesis is that HO-1 overexpression ameliorates fatty liver development.
  
  
  METHODS
  Obese mice were administered cobalt protoporphyrin (CoPP) and stannic mesoporphyrin (SnMP) for 6 weeks. Heme, HO-1, HO activity, PGC1α, FGF21, glycogen content, and lipogenesis were assessed.
  
  
  RESULTS
  CoPP administration increased hepatic HO-1 protein levels and HO activity, decreased hepatic heme, body weight gain, glucose levels, and resulted in decreased steatosis. Increased levels of HO-1 produced a decrease in lipid droplet size, Fatty acid synthase (FAS) levels involving recruitment of FGF21, PPARα, and Glut 1. These beneficial effects were reversed by inhibition of HO activity.
  
  
  CONCLUSIONS
  Increased levels of HO-1 and HO activity reduced the levels of obesity by reducing hepatic heme and lipid accumulation. These changes were manifested by decreases in cellular heme, increases in FGF21, glycogen content, and fatty liver. The beneficial effect of HO-1 induction results from an increase in PPARα and FGF21 levels and a decrease in PGC1α, levels they were reversed by SnMP. Low levels of HO-1 and HO activity are responsible for fatty liver.
authors.affiliation: Department of Medicine, Joan C. Edwards School of Medicine, Marshall University, Huntington, West Virginia, USA.
authors.forename: Terry D
authors.initials: TD
authors.lastname: Hinds
authors.forename: Komal
authors.initials: K
authors.lastname: Sodhi
authors.forename: Charles
authors.initials: C
authors.lastname: Meadows
authors.forename: Larisa
authors.initials: L
authors.lastname: Fedorova
authors.forename: Nitin
authors.initials: N
authors.lastname: Puri
authors.forename: Dong Hyun
authors.initials: DH
authors.lastname: Kim
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Peterson
authors.forename: Joseph
authors.initials: J
authors.lastname: Shapiro
authors.forename: Nader G
authors.initials: NG
authors.lastname: Abraham
authors.forename: Attallah
authors.initials: A
authors.lastname: Kappas
mesh_terms: D050154:Adiposity / Q000502:physiology; D000818:Animals; D005234:Fatty Liver / Q000378:metabolism*; D005346:Fibroblast Growth Factors / Q000235:genetics / Q000378:metabolism*; D051272:Glucose Transporter Type 1 / Q000235:genetics / Q000378:metabolism; D006003:Glycogen / Q000378:metabolism; D006418:Heme / Q000378:metabolism*; D051547:Heme Oxygenase-1 / Q000235:genetics / Q000378:metabolism*; D020738:Leptin / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D008652:Mesoporphyrins / Q000008:administration & dosage; D051379:Mice; D008820:Mice, Obese; D009765:Obesity / Q000188:drug therapy / Q000378:metabolism; D047493:PPAR alpha / Q000235:genetics / Q000378:metabolism; D011524:Protoporphyrins / Q000008:administration & dosage; D017971:Tin Compounds / Q000008:administration & dosage; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D015430:Weight Gain / Q000187:drug effects
chemical_list: D051272:Glucose Transporter Type 1; D020738:Leptin; D008565:Membrane Proteins; D008652:Mesoporphyrins; D047493:PPAR alpha; D011524:Protoporphyrins; C495678:Slc2a1 protein, mouse; D017971:Tin Compounds; D014157:Transcription Factors; C414620:fibroblast growth factor 21; D006418:Heme; D005346:Fibroblast Growth Factors; C007095:cobaltiprotoporphyrin; D006003:Glycogen; D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse