Sonic hedgehog is an autocrine viability factor for myofibroblastic hepatic stellate cells.

Published

Journal Article

BACKGROUND/AIMS: Factors released during liver injury, such as platelet derived growth factor-BB (PDGF), promote accumulation of myofibroblastic hepatic stellate cells (MFB) that drive the pathogenesis of cirrhosis. The hedgehog (Hh) pathway regulates remodeling of other injured tissues. This study evaluates the hypothesis that autocrine production of Sonic hedgehog (Shh) promotes MFB growth. METHODS: Primary rat hepatic stellate cells (HSC) were treated without or with PDGF, a pharmacologic inhibitor of PDGF-regulated kinases, adenovirus expressing activated or dominant negative AKT, or Hh signaling inhibitors. Shh production, expression of Hh inhibitors and target genes, and HSC growth were assessed. RESULTS: HSC expressed Shh, Hh pathway components, and the Hh inhibitor, Hip. During culture Hip expression fell, Shh production increased, and Hh target gene expression was induced. Neutralizing Shh antibodies promoted apoptosis. Adding PDGF increased Shh expression and MFB growth. Both processes followed activation of AKT and were abrogated by AKT inhibitors. Adenoviral delivery of activated AKT up-regulated Shh expression, demonstrating a direct role for AKT in regulating Shh expression. Shh-neutralizing antibodies and other Hh pathway inhibitors blocked the mitogenic effects of PDGF. CONCLUSIONS: These results identify Shh as an autocrine growth factor for MFB and suggest a role for Hh signaling in the pathogenesis of cirrhosis.

Full Text

Duke Authors

Cited Authors

  • Yang, L; Wang, Y; Mao, H; Fleig, S; Omenetti, A; Brown, KD; Sicklick, JK; Li, Y-X; Diehl, AM

Published Date

  • January 2008

Published In

Volume / Issue

  • 48 / 1

Start / End Page

  • 98 - 106

PubMed ID

  • 18022723

Pubmed Central ID

  • 18022723

International Standard Serial Number (ISSN)

  • 0168-8278

Digital Object Identifier (DOI)

  • 10.1016/j.jhep.2007.07.032

Language

  • eng

Conference Location

  • Netherlands