Anti-adipogenic regulation underlies hepatic stellate cell transdifferentiation.
Cirrhosis is the most important consequence of alcoholic liver disease for which liver transplantation is the only treatment option available. Transdifferentiation of hepatic stellate cells (HSC) to myofibroblastic cells (MF) is a central event in liver fibrogenesis, and understanding molecular mechanisms that underlie this cellular event provides pivotal insights into development of new therapeutic modalities for cirrhosis. To this end, the authors proposed several years ago that transdifferentiation of quiescent HSC to MF may be causally associated with transcriptional regulation known for adipocyte-preadipocytic fibroblast dedifferentiation. In support of this notion, the authors showed that adipogenic transcription factors and their downstream adipocyte specific genes are expressed abundantly in quiescent HSC and that this expression profile is lost in HM. Further, gain-of-function manipulations for adipogenic transcription factors such as peroxisome proliferator-activated receptor-gamma (PPAR-gamma) and sterol regulatory element binding protein-1c have been shown to reverse culture-induced MF to quiescent HSC. The authors also demonstrated that tumor necrosis factor-alpha and Wnt, known mediators of anti-adipogenesis, also suppress the activity of PPAR-gamma and contribute to HSC-MF transdifferentiation. These results reinforce the concept of adipogenic regulation essential to the quiescent phenotype and the loss of such regulation underlying HSC-HM transdifferentiation. They also provide insights into the molecular basis for the use of PPAR-gamma agonists, which has been advocated for treatment of liver fibrosis.
Tsukamoto
Hidekazu
H
Department of Pathology, Keck School of Medicine of the University of Southern California, California, USA. htsukamo@usc.edu
She
Hongyun
H
Hazra
Saswati
S
Cheng
Jason
J
Miyahara
Takeo
T
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*; D008103:Liver Cirrhosis / Q000473:pathology*; D008954:Models, Biological; D010100:Oxygen / Q000378:metabolism; D047495:PPAR gamma / Q000378:metabolism; D010641:Phenotype; D051381:Rats; 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
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