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HORMONES AND SIGNALING

Curcumin suppresses the expression of extracellular matrix genes in activated hepatic stellate cells by inhibiting gene expression of connective tissue growth factor

¹Department of Pathology and ²Department of Cellular Biology and Anatomy, Louisiana State University Health Sciences Center, Shreveport, Louisiana; and ³Department of Pharmacology, Nanjing Medical University, Nanjing, China

Submitted 25 September 2005 ; accepted in final form 20 November 2005

Upon liver injury, quiescent hepatic stellate cells (HSCs), the most relevant cell type for hepatic fibrogenesis, become active and overproduce extracellular matrix (ECM). Connective tissue growth factor (CTGF) promotes ECM production. Overexpression of CTGF during hepatic fibrogenesis is induced by transforming growth factor (TGF)-. We recently demonstrated that curcumin reduced cell growth and inhibited ECM gene expression in activated HSCs. Curcumin induced gene expression of peroxisome proliferator-activated receptor (PPAR)- and stimulated its activity in activated HSCs, which was required for curcumin to suppress ECM gene expression, including I(I)-collagen. The underlying mechanisms remain largely unknown. The aim of this study was to elucidate the mechanisms by which curcumin suppresses I(I)-collagen gene expression in activated HSCs. We hypothesize that inhibition of I(I)-collagen gene expression in HSCs by curcumin is mediated by suppressing CTGF gene expression through attenuating oxidative stress and interrupting TGF- signaling. The present report demonstrated that curcumin significantly reduced the abundance of CTGF in passaged HSCs and suppressed its gene expression. Exogenous CTGF dose dependently abrogated the inhibitory effect of curcumin. Activation of PPAR- by curcumin resulted in the interruption of TGF- signaling by suppressing gene expression of TGF- receptors, leading to inhibition of CTGF gene expression. The phytochemical showed its potent antioxidant property by significantly increasing the level of total glutathione (GSH) and the ratio of GSH to GSSG in activated HSCs. De novo synthesis of cellular GSH was a prerequisite for curcumin to interrupt TGF- signaling and inhibited gene expression of CTGF and I(I)-collagen in activated HSCs. Taken together, our results demonstrate that inhibition of I(I)-collagen gene expression by curcumin in activated HSCs results from suppression of CTGF gene expression through increasing cellular GSH contents and interruption of TGF- signaling. These results provide novel insights into the mechanisms underlying inhibition of HSC activation by curcumin.

collagen; fibrogenesis; phytochemicals; signal transduction; oxidative stress

This article has been cited by other articles:

				Y. Fu, S. Zheng, J. Lin, J. Ryerse, and A. Chen Curcumin Protects the Rat Liver from CCl4-Caused Injury and Fibrogenesis by Attenuating Oxidative Stress and Suppressing Inflammation Mol. Pharmacol., February 1, 2008; 73(2): 399 - 409. [Abstract] [Full Text] [PDF]

				S. Zheng and A. Chen Disruption of transforming growth factor-beta signaling by curcumin induces gene expression of peroxisome proliferator-activated receptor-{gamma} in rat hepatic stellate cells Am J Physiol Gastrointest Liver Physiol, January 1, 2007; 292(1): G113 - G123. [Abstract] [Full Text] [PDF]