1. ¹Department of Cellular Biology & Anatomy, Louisiana State University Health Sciences Center in Shreveport, Shreveport, LA, USA
2. ²Department of Pathology, Louisiana State University Health Sciences Center in Shreveport, Shreveport, LA, USA

Correspondence: Dr A Chen PhD, Department of Pathology, Louisiana State University Health Sciences Center in Shreveport, 1501 Kings Hwy, Shreveport, LA 71130, USA. E-mail: achen@lsuhsc.edu

Received 2 February 2006; Revised 15 March 2006; Accepted 20 March 2006; Published online 8 May 2006.

Abstract

Hepatic stellate cells (HSC) are the major players during hepatic fibrogenesis. Overproduction of extracellular matrix (ECM) is a characteristic of activated HSC. Transforming growth factor-beta (TGF-) is the most potent fibrogenic cytokine while connective tissue growth factor (CTGF) mediates the production of TGF--induced ECM in activated HSC. HSC activation and hepatic fibrogenesis are stimulated by oxidative stress. Glutathione (GSH) is the most important intracellular antioxidant. The aim of this study is to explore the mechanisms of (-)-epigallocatechin-3-gallate (EGCG), the major and most active component in green tea extracts, in the inhibition of ECM gene expression in activated HSC. It is hypothesized that EGCG inhibits ECM gene expression in activated HSC by interrupting TGF- signaling through attenuating oxidative stress. It is found that EGCG interrupts TGF- signaling in activated HSC by suppressing gene expression of type I and II TGF- receptors. EGCG inhibits CTGF gene expression, leading to the reduction in the abundance of ECM, including I(I) procollagen. Exogenous CTGF dose dependently eliminates the antifibrogenic effect. EGCG attenuates oxidative stress in passaged HSC by scavenging reactive oxygen species and reducing lipid peroxidation. De novo synthesis of GSH is a prerequisite for EGCG to interrupt TGF- signaling and to reduce the abundance of I(I) procollagen in activated HSC in vitro. Taken together, our results demonstrate that the interruption of TGF- signaling by EGCG results in the suppression of gene expression of CTGF and ECM in activated HSC in vitro. In addition, our results, for the first time, demonstrate that the antioxidant property of EGCG derived from de novo synthesis of intracellular GSH plays a critical role in its antifibrogenic effect. These results provide novel insights into the mechanisms of EGCG as an antifibrogenic candidate in the prevention and treatment of liver fibrosis.