title: Enhanced expression of BMP6 inhibits hepatic fibrosis in non-alcoholic fatty liver disease.
abstract: OBJECTIVE
  Bone morphogenetic protein 6 (BMP6) has been identified as crucial regulator of iron homeostasis. However, its further role in liver pathology including non-alcoholic fatty liver disease (NAFLD) and its advanced form non-alcoholic steatohepatitis (NASH) is elusive. The aim of this study was to investigate the expression and function of BMP6 in chronic liver disease.
  
  
  METHODS
  BMP6 was analysed in hepatic samples from murine models of chronic liver injury and patients with chronic liver diseases. Furthermore, a tissue microarray comprising 110 human liver tissues with different degree of steatosis and inflammation was assessed. BMP6-deficient (BMP6(-/-)) and wild-type mice were compared in two dietary NASH-models, that is, methionine choline-deficient (MCD) and high-fat (HF) diets.
  
  
  RESULTS
  BMP6 was solely upregulated in NAFLD but not in other murine liver injury models or diseased human livers. In NAFLD, BMP6 expression correlated with hepatic steatosis but not with inflammation or hepatocellular damage. Also, in vitro cellular lipid accumulation in primary human hepatocytes induced increased BMP6 expression. MCD and HF diets caused more hepatic inflammation and fibrosis in BMP6(-/-) compared with wild-type mice. However, only in the MCD and not in the HF diet model BMP6(-/-) mice developed marked hepatic iron overload, suggesting that further mechanisms are responsible for protective BMP6 effect. In vitro analysis revealed that recombinant BMP6 inhibited the activation of hepatic stellate cells (HSCs) and reduced proinflammatory and profibrogenic gene expression in already activated HSCs.
  
  
  CONCLUSIONS
  Steatosis-induced upregulation of BMP6 in NAFLD is hepatoprotective. Induction of BMP6-signalling may be a promising antifibrogenic strategy.
authors.affiliation: Institute of Pathology, University Regensburg, Regensburg, Germany.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Arndt
authors.affiliation: Institute of Pathology, University Regensburg, Regensburg, Germany.
authors.forename: Eva
authors.initials: E
authors.lastname: Wacker
authors.affiliation: Department of Internal Medicine I, University Hospital Regensburg, Regensburg, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Dorn
authors.affiliation: Department of Internal Medicine I, University Hospital Regensburg, Regensburg, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Koch
authors.affiliation: Department of Internal Medicine I, University Hospital Regensburg, Regensburg, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Saugspier
authors.affiliation: Grosshadern Tissue Bank and Center for Liver Cell Research, Department of Surgery, Ludwig-Maximilians-University Munich, Munich, Germany.
authors.forename: Wolfgang E
authors.initials: WE
authors.lastname: Thasler
authors.affiliation: Institute of Pathology, University Hospital Erlangen, Erlangen, Germany.
authors.forename: Arndt
authors.initials: A
authors.lastname: Hartmann
authors.affiliation: Institute of Pathology, University Regensburg, Regensburg, Germany.
authors.forename: Anja Katrin
authors.initials: AK
authors.lastname: Bosserhoff
authors.affiliation: Department of Internal Medicine I, University Hospital Regensburg, Regensburg, Germany.
authors.forename: Claus
authors.initials: C
authors.lastname: Hellerbrand
mesh_terms: D000818:Animals; D055418:Bone Morphogenetic Protein 6 / Q000172:deficiency / Q000378:metabolism*; D002478:Cells, Cultured; D004195:Disease Models, Animal; D018450:Disease Progression; D005355:Fibrosis / Q000209:etiology / Q000378:metabolism* / Q000517:prevention & control*; D055166:Hepatic Stellate Cells / Q000378:metabolism; D019694:Hepatitis B, Chronic / Q000378:metabolism; D019698:Hepatitis C, Chronic / Q000378:metabolism; D006801:Humans; D007501:Iron / Q000032:analysis; D008099:Liver / Q000737:chemistry / Q000473:pathology*; D008104:Liver Cirrhosis, Alcoholic / Q000378:metabolism; D008565:Membrane Proteins; D051379:Mice; D065626:Non-alcoholic Fatty Liver Disease / Q000150:complications* / Q000378:metabolism*; D020011:Protective Agents / Q000378:metabolism*; D014280:Triglycerides / Q000032:analysis
chemical_list: C452880:Atp5md protein, rat; D055418:Bone Morphogenetic Protein 6; D008565:Membrane Proteins; D020011:Protective Agents; D014280:Triglycerides; D007501:Iron
keywords: Fatty Liver; Fibrogenesis; Hepatic Stellate Cell