Non-alcoholic steatohepatitis pathogenesis: role of repair in regulating the disease progression.

Published

Journal Article

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. CONCLUSION: 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.

Full Text

Duke Authors

Cited Authors

  • Jung, Y; Diehl, AM

Published Date

  • 2010

Published In

Volume / Issue

  • 28 / 1

Start / End Page

  • 225 - 228

PubMed ID

  • 20460916

Pubmed Central ID

  • 20460916

Electronic International Standard Serial Number (EISSN)

  • 1421-9875

Digital Object Identifier (DOI)

  • 10.1159/000282092

Language

  • eng

Conference Location

  • Switzerland