Gene expression profile of quiescent and activated rat hepatic stellate cells implicates Wnt signaling pathway in activation.
OBJECTIVE
Liver fibrosis is characterized by accumulation of extracellular matrix proteins synthesized by activated hepatic stellate cells (HSCs). To understand molecular mechanisms of HSCs activation a comprehensive comparison of gene expression between quiescent and activated HSCs is needed.


METHODS
Using DNA microarrays we compared expression of 31,100 genes between quiescent rat HSCs and culture activated rat HSCs. Expression of the components of Wnt signaling was analyzed in HSCs and fibrotic livers by RT-PCR. Activation of beta-catenin was analyzed by Western blot.


RESULTS
Nine hundred genes were upregulated more than 4.6-fold and 500 genes were downregulated more than 5.7-fold in activated HSCs. The upregulated genes included Wnt receptor frizzled 2, ligands Wnt4 and Wnt5, which was confirmed in fibrotic livers. Expression of the target genes of Wnt signaling was increased from 5- to 70-fold. Phosphorylation and nuclear translocation of beta-catenin were unchanged, indicating activation of the noncanonical Wnt pathway.


CONCLUSIONS
Highly upregulated expression of Wnt5a and its receptor frizzled 2 implicates this pathway in differentiation of quiescent HSCs into myofibroblasts. Activation of Wnt signaling pathway in HSCs and in animal models of liver fibrosis has not been described previously, suggesting an important role of Wnt signaling in development of liver fibrosis.
Jiang
Feng
F
Department of Biomedical Sciences, Florida State University College of Medicine, Tallahassee, FL 32306, USA.
Parsons
Christopher J
CJ
Stefanovic
Branko
B
D000818:Animals; D002251:Carbon Tetrachloride; D002454:Cell Differentiation; D002478:Cells, Cultured; D004247:DNA / Q000235:genetics; D015536:Down-Regulation / Q000235:genetics; D005347:Fibroblasts; D051157:Frizzled Receptors / Q000235:genetics / Q000378:metabolism; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D008099:Liver / Q000166:cytology* / Q000378:metabolism*; D008103:Liver Cirrhosis / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics*; D015854:Up-Regulation / Q000235:genetics; D051153:Wnt Proteins / Q000235:genetics* / Q000378:metabolism*; D000071818:Wnt-5a Protein; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism
D051157:Frizzled Receptors; D043562:Receptors, G-Protein-Coupled; D051153:Wnt Proteins; D000071818:Wnt-5a Protein; C491837:Wnt5a protein, rat; D051176:beta Catenin; C078604:Fzd2 protein, rat; D004247:DNA; D002251:Carbon Tetrachloride; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat