Journal of Biological Chemistry
Volume 280, Issue 6, 11 February 2005, Pages 4959-4967
Journal home page for Journal of Biological Chemistry

Molecular Basis of Cell and Developmental Biology
Adipogenic Transcriptional Regulation of Hepatic Stellate Cells*

https://doi.org/10.1074/jbc.M410078200Get rights and content
Under a Creative Commons license
open access

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 γ (PPARγ) 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) α, C/EBPβ, C/EBPδ, PPARγ, liver X receptor α, sterol regulatory element-binding protein 1c and of adipocyte-specific genes in the quiescent cells. Conversely, activated HSC have increased expression of PPARβ, 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 PPARγ or SREBP-1c in these cells, induces a panel of adipogenic transcription factors, reduces PPARβ, 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.

Cited by (0)

*

This work is supported by National Institutes of Health Grants R37 AA006603, P50 AA11999, R24 AA12885 (Non-Parenchymal Liver Cell Core), and P30 DK48522 (Molecular Biology and Confocal Microscopy Cores) and by the Medical Research Service of Department of Veterans Affairs. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.