scholarly journals Peroxisome Proliferator-activated Receptor γ Induces a Phenotypic Switch from Activated to Quiescent Hepatic Stellate Cells

2003 ◽  
Vol 279 (12) ◽  
pp. 11392-11401 ◽  
Author(s):  
Saswati Hazra ◽  
Shigang Xiong ◽  
Jiaohong Wang ◽  
Richard A. Rippe ◽  
V. Krishna ◽  
...  
Keyword(s):  
Hepatic Stellate Cells ◽  
Stellate Cells ◽  
Peroxisome Proliferator ◽  
Phenotypic Switch ◽  
Peroxisome Proliferator Activated Receptor

Disruption of transforming growth factor-β signaling by curcumin induces gene expression of peroxisome proliferator-activated receptor-γ in rat hepatic stellate cells

2007 ◽  
Vol 292 (1) ◽  
pp. G113-G123 ◽  
Author(s):  
Shizhong Zheng ◽  
Anping Chen
Keyword(s):  
Gene Expression ◽  
Hepatic Stellate Cells ◽  
Molecular Mechanisms ◽  
Transforming Growth Factor ◽  
Gene Promoter ◽  
Stellate Cells ◽  
Transforming Growth Factor Β ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Ppar Γ

Activation of hepatic stellate cells (HSC), the major effectors of hepatic fibrogenesis, is coupled with sequential alterations in gene expression, including an increase in receptors for transforming growth factor-β (TGF-β) and a dramatic reduction in the peroxisome proliferator-activated receptor-γ (PPAR-γ). The relationship between them remains obscure. We previously demonstrated that curcumin induced gene expression of PPAR-γ in activated HSC, leading to reducing cell proliferation, inducing apoptosis and suppressing expression of extracellular matrix genes. The underlying molecular mechanisms are largely unknown. We recently observed that stimulation of PPAR-γ activation suppressed gene expression of TGF-β receptors in activated HSC, leading to the interruption of TGF-β signaling. This observation supported our assumption of an antagonistic relationship between PPAR-γ activation and TGF-β signaling in HSC. In this study, we further hypothesize that TGF-β signaling might negatively regulate gene expression of PPAR-γ in activated HSC. The present report demonstrates that exogenous TGF-β1 inhibits gene expression of PPAR-γ in activated HSC, which is eliminated by the pretreatment with curcumin likely by interrupting TGF-β signaling. Transfection assays further indicate that blocking TGF-β signaling by dominant negative type II TGF-β receptor increases the promoter activity of PPAR-γ gene. Promoter deletion assays, site-directed mutageneses, and gel shift assays localize two Smad binding elements (SBEs) in the PPAR-γ gene promoter, acting as curcumin response elements and negatively regulating the promoter activity in passaged HSC. The Smad3/4 protein complex specifically binds to the SBEs. Overexpression of Smad4 dose dependently eliminates the inhibitory effects of curcumin on the PPAR-γ gene promoter and TGF-β signaling. Taken together, these results demonstrate that the interruption of TGF-β signaling by curcumin induces gene expression of PPAR-γ in activated HSC in vitro. Our studies provide novel insights into the molecular mechanisms of curcumin in the induction of PPAR-γ gene expression and in the inhibition of HSC activation.

Tumor necrosis factor-α inhibits peroxisome proliferator-activated receptor γ activity at a posttranslational level in hepatic stellate cells

2004 ◽  
Vol 286 (5) ◽  
pp. G722-G729 ◽  
Author(s):  
Chin K. Sung ◽  
Hongyun She ◽  
Shigang Xiong ◽  
Hidekazu Tsukamoto
Keyword(s):  
Hepatic Stellate Cells ◽  
Stellate Cells ◽  
Luciferase Reporter ◽  
Critical Event ◽  
Peroxisome Proliferator ◽  
Mrna Levels ◽  
Luciferase Reporter Gene ◽  
Mobility Shift ◽  
Peroxisome Proliferator Activated Receptor ◽  
Tnf Α

Diminished activity of peroxisome proliferator-activated receptor γ (PPARγ) is implicated in activation of hepatic stellate cells (HSC), a critical event in the development of liver fibrosis. In the present study, we investigated PPARγ regulation by TNF-α in an HSC line designated as BSC. In BSC, TNF-α decreased both basal and ligand (GW1929)-induced PPARγ mRNA levels without changing its protein expression. Nuclear extracts from BSC treated with TNF-α showed decreased binding of PPARγ to PPAR-responsive element (PPRE) as determined by electrophoretic mobility shift assay. In BSC transiently transfected with a PPARγ1 expression vector and a PPRE-luciferase reporter gene, TNF-α decreased both basal and GW1929-induced transactivation of the PPRE promoter. TNF-α increased activation of ERK1/2 and JNK, previously implicated in phosphorylation of Ser82 of PPARγ1 and resultant negative regulation of PPARγ transactivity. In fact, TNF-α failed to inhibit transactivity of a Ser82Ala PPARγ1 mutant in BSC. TNF-α-mediated inhibition of PPARγ transactivity was not blocked with a Ser32Ala/Ser36Ala mutant of inhibitory NF-κBα (IκBα). These results suggest that TNF-α inhibits PPARγ transactivity in cultured HSC, at least in part, by diminished PPARγ-PPRE (DNA) binding and ERK1/2-mediated phosphorylation of Ser82 of PPARγ1, but not via the NF-κB pathway.

Peroxisome proliferator-activated receptor Γ(PPAΓ) modulates hepatic stellate cells activation

2000 ◽  
Vol 118 (4) ◽  
pp. A910 ◽  
Author(s):  
Andrea Galli ◽  
David W. Crabb ◽  
Elisabetta Ceni ◽  
Renata Salzano ◽  
Tommaso Mello ◽  
...  
Keyword(s):  
Hepatic Stellate Cells ◽  
Stellate Cells ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor
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