| Sonic hedgehog is an autocrine viability factor for myofibroblastic hepatic stellate cells. | |
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MedLine Citation:
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PMID: 18022723 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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. |
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Authors:
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Liu Yang; Ying Wang; Hua Mao; Susanne Fleig; Alessia Omenetti; Kevin D Brown; Jason K Sicklick; Yin-Xiong Li; Anna Mae Diehl |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural Date: 2007-10-18 |
Journal Detail:
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Title: Journal of hepatology Volume: 48 ISSN: 0168-8278 ISO Abbreviation: J. Hepatol. Publication Date: 2008 Jan |
Date Detail:
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Created Date: 2007-12-10 Completed Date: 2008-03-11 Revised Date: 2010-12-20 |
Medline Journal Info:
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Nlm Unique ID: 8503886 Medline TA: J Hepatol Country: England |
Other Details:
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Languages: eng Pagination: 98-106 Citation Subset: IM |
Affiliation:
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Gastroenterology and Medicine, Duke University Medical Center, Durham, NC 27710, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Adenoviridae Animals Antimetabolites / diagnostic use Autocrine Communication / physiology* Blotting, Western Bromodeoxyuridine / diagnostic use Caspase 3 / biosynthesis Caspase 7 / biosynthesis Cell Proliferation / drug effects Cell Separation Fibroblasts / pathology* Fluorescent Antibody Technique Genes, Reporter / genetics Hedgehog Proteins / genetics* Hepatocytes / pathology* Ligands Liver / metabolism, pathology* Oncogene Protein v-akt / physiology Pericytes / drug effects, pathology* Platelet-Derived Growth Factor / genetics, physiology RNA, Messenger / biosynthesis, genetics Rats Reverse Transcriptase Polymerase Chain Reaction Transduction, Genetic Transfection |
| Grant Support | |
ID/Acronym/Agency:
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5R01AA010154/AA/NIAAA NIH HHS; R01 AA010154-11/AA/NIAAA NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Antimetabolites; 0/Hedgehog Proteins; 0/Ligands; 0/Platelet-Derived Growth Factor; 0/RNA, Messenger; 59-14-3/Bromodeoxyuridine; EC 2.7.11.1/Oncogene Protein v-akt; EC 3.4.22.-/Caspase 3; EC 3.4.22.-/Caspase 7 |
| Comments/Corrections | |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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