RGD Reference Report - Wnt antagonism inhibits hepatic stellate cell activation and liver fibrosis. - Rat Genome Database

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Wnt antagonism inhibits hepatic stellate cell activation and liver fibrosis.

Authors: Cheng, JH  She, H  Han, YP  Wang, J  Xiong, S  Asahina, K  Tsukamoto, H 
Citation: Cheng JH, etal., Am J Physiol Gastrointest Liver Physiol. 2008 Jan;294(1):G39-49. Epub 2007 Nov 15.
RGD ID: 4110127
Pubmed: PMID:18006602   (View Abstract at PubMed)
DOI: DOI:10.1152/ajpgi.00263.2007   (Journal Full-text)

Activation of hepatic stellate cells (HSC), a key event in liver fibrosis, is caused by diminished adipogenic transcription. This study investigated whether Wnt signaling contributes to "antiadipogenic" activation of HSC and liver fibrogenesis. Culture-activated HSC from normal rats and HSC from cholestatic rat livers were examined for expression of Wnt, Frizzled (Fz) receptors, and coreceptors by quantitative PCR. Wnt signaling was assessed by nuclear beta-catenin and T cell factor (TCF) promoter activity. Dickkopf-1 (Dkk-1), a Wnt coreceptor antagonist, was transduced by an adenoviral vector to assess the effects of Wnt antagonism on culture activation of HSC and cholestatic liver fibrosis in mice. Messenger RNA for canonical (Wnt3a and 10b) and noncanonical (Wnt4 and 5a) Wnt genes, Fz-1 and 2, and coreceptors [low-density lipoprotein-receptor-related protein (LRP)6 and Ryk] are increased approximately 3-12-fold in culture-activated HSC compared with quiescent HSC. The nuclear beta-catenin level and TCF DNA binding are markedly increased in activated HSC. TCF promoter activity is stimulated with Wnt1 but inhibited by Chibby, a protein that blocks beta-catenin interaction with TCF, and by Dkk-1. Dkk-1 enhances peroxisome proliferator-activated receptor-gamma (PPARgamma)-driven PPAR response element (PPRE) promoter activity, a key adipogenic transcriptional parameter, abrogates agonist-stimulated contraction, and restores HSC quiescence in culture. High expression of Dkk-1 increases apoptosis of cultured HSC. Expression of Wnt and Fz genes is also induced in HSC isolated from experimental cholestatic liver fibrosis, and Dkk-1 expression ameliorates this form of liver fibrosis in mice. These results demonstrate antiadipogenic Wnt signaling in HSC activation and therapeutic potential of Wnt antagonism for liver fibrosis.



RGD Manual Disease Annotations    Click to see Annotation Detail View

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
LRP6HumanExperimental Liver Cirrhosis  ISOLrp6 (Mus musculus) RGD 
Lrp6RatExperimental Liver Cirrhosis  ISOLrp6 (Mus musculus) RGD 
Lrp6MouseExperimental Liver Cirrhosis  IMP  RGD 

Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process

  
Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
Lrp6Ratcanonical Wnt signaling pathway  IMP  RGD 
Lrp6Ratcell-cell adhesion  IMP  RGD 
Lrp6Ratregulation of DNA-templated transcription  IMP  RGD 

Objects Annotated

Genes (Rattus norvegicus)
Lrp6  (LDL receptor related protein 6)

Genes (Mus musculus)
Lrp6  (low density lipoprotein receptor-related protein 6)

Genes (Homo sapiens)
LRP6  (LDL receptor related protein 6)


Additional Information