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PMID: 15320868 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, P.H.S.

Activation of PPARgamma is required for curcumin to induce apoptosis and to inhibit the expression of extracellular matrix genes in hepatic stellate cells in vitro.

The Biochemical journal ·Vol. 384 ·No. Pt 1 ·2004-11-15 ·Pages 149-57

Zheng S, Chen A

Abstract

During liver fibrogenesis, quiescent HSC (hepatic stellate cells) become active, a transformation that is associated with enhanced cell proliferation and overproduction of ECM (extracellular matrix). Inhibition of cell proliferation and induction of apoptosis are potential strategies to block the activation of HSC for the prevention and treatment of liver fibrosis. Levels of PPARgamma (peroxisome proliferator-activated receptor gamma) are dramatically diminished in parallel with HSC activation. Stimulation of PPARgamma by its agonists inhibits HSC activation in vitro and in vivo. We demonstrated recently that curcumin, the yellow pigment in curry, inhibited HSC activation in vitro, reducing cell proliferation, inducing apoptosis and inhibiting ECM gene expression. Further studies indicated that curcumin induced the gene expression of PPARgamma and stimulated its activity in activated HSC in vitro, which was required for curcumin to inhibit HSC proliferation. The aims of the present study were to evaluate the roles of PPARgamma activation in the induction of apoptosis and suppression of ECM gene expression by curcumin in activated HSC, and to elucidate the underlying mechanisms. Our results demonstrated that blocking PPARgamma activation abrogated the effects of curcumin on the induction of apoptosis and inhibition of the expression of ECM genes in activated HSC in vitro. Further experiments demonstrated that curcumin suppressed the gene expression of TGF-beta (transforming growth factor-beta) receptors and interrupted the TGF-beta signalling pathway in activated HSC, which was mediated by PPARgamma activation. Taken together, our results demonstrate that curcumin stimulated PPARgamma activity in activated HSC in vitro, which was required for curcumin to reduce cell proliferation, induce apoptosis and suppress ECM gene expression. These results provide novel insight into the mechanisms responsible for the inhibition of HSC activation by curcumin. The characteristics of curcumin, which has no adverse health effects, make it a potential candidate for prevention and treatment of hepatic fibrosis.

MeSH Terms
Animals Apoptosis/drug effects,physiology Cell Proliferation Curcumin/metabolism,pharmacology Cyclin D1/antagonists & inhibitors Enzyme Inhibitors/pharmacology Extracellular Matrix/genetics Flow Cytometry/methods Gene Expression Regulation/drug effects,genetics Liver/chemistry,cytology,metabolism Male Nitro Compounds/pharmacology PPAR gamma/antagonists & inhibitors,metabolism Rats Rats, Sprague-Dawley Receptors, Transforming Growth Factor beta/genetics Signal Transduction/drug effects,physiology Thiazoles/pharmacology Transforming Growth Factor beta/antagonists & inhibitors,physiology Transforming Growth Factor beta1
Chemicals
Enzyme Inhibitors Nitro Compounds PD 068235 PPAR gamma Receptors, Transforming Growth Factor beta Tgfb1 protein, rat Thiazoles Transforming Growth Factor beta Transforming Growth Factor beta1 Cyclin D1 Curcumin
Authors & Affiliations
2 authors, click to expand affiliations / ORCID
Zheng Shizhong
Department of Pathology, Louisiana State University Health Sciences Center in Shreveport, Shreveport, LA 71130, USA.
Chen Anping
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Article Info
Journal
The Biochemical journal
Abbr.
Biochem J
ISSN
1470-8728
DOI
10.1042/BJ20040928
Published
2004-11-15
Pages
149-57
Language
English
Region
England
NLM ID
2984726R
PMCID
PMC1134098
Subset
IM
Grants
NIDDK NIH HHS · R01 DK047995 · United States
NIDDK NIH HHS · DK 47995 · United States
External Links
PubMed source DOI: 10.1042/BJ20040928 PMC Full Text View journal details
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