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

Publication ,  Journal Article
Yang, L; Wang, Y; Mao, H; Fleig, S; Omenetti, A; Brown, KD; Sicklick, JK; Li, Y-X; Diehl, AM
Published in: J Hepatol
January 2008

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.

Duke Scholars

Published In

J Hepatol

DOI

ISSN

0168-8278

Publication Date

January 2008

Volume

48

Issue

1

Start / End Page

98 / 106

Location

Netherlands

Related Subject Headings

  • Transfection
  • Transduction, Genetic
  • Reverse Transcriptase Polymerase Chain Reaction
  • Rats
  • RNA, Messenger
  • Platelet-Derived Growth Factor
  • Pericytes
  • Oncogene Protein v-akt
  • Liver
  • Ligands
 

Citation

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Chicago
ICMJE
MLA
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Yang, L., Wang, Y., Mao, H., Fleig, S., Omenetti, A., Brown, K. D., … Diehl, A. M. (2008). Sonic hedgehog is an autocrine viability factor for myofibroblastic hepatic stellate cells. J Hepatol, 48(1), 98–106. https://doi.org/10.1016/j.jhep.2007.07.032
Yang, Liu, Ying Wang, Hua Mao, Susanne Fleig, Alessia Omenetti, Kevin D. Brown, Jason K. Sicklick, Yin-Xiong Li, and Anna Mae Diehl. “Sonic hedgehog is an autocrine viability factor for myofibroblastic hepatic stellate cells.J Hepatol 48, no. 1 (January 2008): 98–106. https://doi.org/10.1016/j.jhep.2007.07.032.
Yang L, Wang Y, Mao H, Fleig S, Omenetti A, Brown KD, et al. Sonic hedgehog is an autocrine viability factor for myofibroblastic hepatic stellate cells. J Hepatol. 2008 Jan;48(1):98–106.
Yang, Liu, et al. “Sonic hedgehog is an autocrine viability factor for myofibroblastic hepatic stellate cells.J Hepatol, vol. 48, no. 1, Jan. 2008, pp. 98–106. Pubmed, doi:10.1016/j.jhep.2007.07.032.
Yang L, Wang Y, Mao H, Fleig S, Omenetti A, Brown KD, Sicklick JK, Li Y-X, Diehl AM. Sonic hedgehog is an autocrine viability factor for myofibroblastic hepatic stellate cells. J Hepatol. 2008 Jan;48(1):98–106.
Journal cover image

Published In

J Hepatol

DOI

ISSN

0168-8278

Publication Date

January 2008

Volume

48

Issue

1

Start / End Page

98 / 106

Location

Netherlands

Related Subject Headings

  • Transfection
  • Transduction, Genetic
  • Reverse Transcriptase Polymerase Chain Reaction
  • Rats
  • RNA, Messenger
  • Platelet-Derived Growth Factor
  • Pericytes
  • Oncogene Protein v-akt
  • Liver
  • Ligands