title: Non-alcoholic steatohepatitis pathogenesis: role of repair in regulating the disease progression.
abstract: BACKGROUND
  Increased hepatocyte apoptosis distinguishes non-alcoholic steatohepatitis (NASH) from non-alcoholic fatty liver disease (NAFLD). Therefore, we postulated that outcomes of NASH depended upon whether or not hepatic regenerative responses could keep pace with the increased rate of hepatocyte death.
  
  
  METHODS
  To investigate mechanisms that the liver deploys to compensate for increased hepatocyte apoptosis, we studied a transgenic mouse model in which hepatocyte vulnerability to apoptosis was increased due to disruption of NF-kappaB survival signaling.
  
  
  RESULTS
  We learned that hepatocyte death is coupled to the expansion of cell types that are involved in liver repair, including progenitors and myofibroblasts, and discovered that the outgrowth of these cell types occurs, at least in part, because dying hepatocytes produce Hedgehog morphogens that enhance the growth of progenitor and myofibroblast populations. The clinical significance of this discovery is supported by evidence that the degree of Hedgehog pathway activation also parallels the severity of liver fibrosis in patients with NASH, a disease in which hepatocyte apoptotic activity has been strongly linked to fibrosis progression.
  
  
  CONCLUSIONS
  The data generated by studying a mouse model of chronic hepatocyte apoptosis, as well as NASH, a common human liver disease that is characterized by increased rates of hepatocyte apoptosis, are very similar. Both strongly support the concept that repair responses play an important role in controlling the outcomes of NASH.
authors.affiliation: Division of Gastroenterology, Duke University, Durham, NC 27710, USA.
authors.forename: Youngmi
authors.initials: Y
authors.lastname: Jung
authors.forename: Anna Mae
authors.initials: AM
authors.lastname: Diehl
mesh_terms: D000818:Animals; D017209:Apoptosis; D049109:Cell Proliferation; D018450:Disease Progression; D005234:Fatty Liver / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D005355:Fibrosis / Q000503:physiopathology; D053823:Hedgehog Proteins; D022781:Hepatocytes / Q000378:metabolism / Q000473:pathology* / Q000502:physiology; D006801:Humans; D008024:Ligands; D008115:Liver Regeneration / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D053823:Hedgehog Proteins; D008024:Ligands; D016328:NF-kappa B