title: Adipogenic transcriptional regulation of hepatic stellate cells.
abstract: Hepatic stellate cells (HSC) undergo transdifferentiation (activation) from lipid-storing pericytes to myofibroblastic cells to participate in liver fibrogenesis. Our recent work demonstrates that depletion of peroxisome proliferator-activated receptor gamma (PPARgamma) constitutes one of the key molecular events for HSC activation and that ectopic expression of this nuclear receptor achieves the phenotypic reversal of activated HSC to the quiescent cells. The present study extends these findings to test a novel hypothesis that adipogenic transcriptional regulation is required for the maintenance of HSC quiescence. Comparative analysis of quiescent and activated HSC in culture reveals higher expression of putative adipogenic transcription factors such as CCAAT/enhancer-binding protein (C/EBP) alpha, C/EBPbeta, C/EBPdelta, PPARgamma, liver X receptor alpha, sterol regulatory element-binding protein 1c and of adipocyte-specific genes in the quiescent cells. Conversely, activated HSC have increased expression of PPARbeta, a transcription factor known to promote fatty acid oxidation. A treatment of activated HSC with the adipocyte differentiation mixture (isobutylmethylxanthine, dexamethasone, and insulin) or ectopic expression of PPARgamma or SREBP-1c in these cells, induces a panel of adipogenic transcription factors, reduces PPARbeta, and causes the phenotypic reversal to quiescent HSC. These results support the importance of adipogenic transcriptional regulation in HSC quiescence and provide a new framework for identifying novel molecular targets for the treatment of liver cirrhosis.
authors.affiliation: Department of Pathology, Keck School of Medicine of the University of Southern California, Los Angeles, California 90033, USA.
authors.forename: Hongyun
authors.initials: H
authors.lastname: She
authors.forename: Shigang
authors.initials: S
authors.lastname: Xiong
authors.forename: Saswati
authors.initials: S
authors.lastname: Hazra
authors.forename: Hidekazu
authors.initials: H
authors.lastname: Tsukamoto
mesh_terms: D017667:Adipocytes / Q000378:metabolism*; D000818:Animals; D022762:CCAAT-Enhancer-Binding Proteins / Q000378:metabolism; D002454:Cell Differentiation; D003470:Culture Media / Q000494:pharmacology; D017931:DNA Primers / Q000737:chemistry; D004268:DNA-Binding Proteins / Q000378:metabolism; D005227:Fatty Acids / Q000378:metabolism; D005355:Fibrosis; D050356:Lipid Metabolism; D008099:Liver / Q000166:cytology* / Q000378:metabolism* / Q000473:pathology; D008954:Models, Biological; D010100:Oxygen / Q000378:metabolism; D047495:PPAR gamma / Q000378:metabolism; D010641:Phenotype; D051381:Rats; D017208:Rats, Wistar; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D051780:Sterol Regulatory Element Binding Protein 1; D013997:Time Factors; D014157:Transcription Factors / Q000378:metabolism; D014158:Transcription, Genetic
chemical_list: D022762:CCAAT-Enhancer-Binding Proteins; D003470:Culture Media; D017931:DNA Primers; D004268:DNA-Binding Proteins; D005227:Fatty Acids; D047495:PPAR gamma; C497389:Srebf1 protein, rat; D051780:Sterol Regulatory Element Binding Protein 1; D014157:Transcription Factors; D010100:Oxygen