Activated hepatic stellate cells (HSC) are the primary source of excessive production of extracellular matrix during liver fibrogenesis. Although the underlying mechanisms remain incompletely understood, it is widely accepted that oxidative stress plays a critical role in liver fibrogenesis. Suppression of HSC growth and activation, as well as induction of apoptosis, have been proposed as therapeutic strategies for treatment and prevention of this disease. In the present report, we elucidated, for the first time, effects of the antioxidant (—)-epigallocatechin-3-gallate (EGCG), a major (and the most active) component of green tea extracts, on cultured HSC growth and activation. Our results revealed that EGCG significantly inhibited cultured HSC growth by inducing cell cycle arrest and apoptosis in a dose- and time-dependent manner. In addition, EGCG markedly suppressed the activation of cultured HSC as demonstrated by blocking transforming growth factor-β signal transduction and by inhibiting the expression of α1(I) collagen, fibronectin and α-smooth muscle actin genes induced by acetaldehyde, the most active metabolite of ethanol. Furthermore, EGCG reacted differently in the inhibition of nuclear factor-κB activity between cultured HSC with or without acetaldehyde stimulation. Taken together, our results indicated that EGCG was a novel and effective inhibitor for activated HSC growth and activation in vitro. Further studies are necessary to evaluate the effect of this polyphenol in prevention of quiescent HSC activation in vivo, and to further elucidate the underlying mechanisms.
- gene regulation
- green tea extract
Abbreviations used: BrdU, bromodeoxyuridine; DMEM, Dulbecco's modified Eagle's medium; ECM, extracellular matrix; EGCG, (—)-epigallocatechin-3-gallate; EMSA, electrophoretic mobility shift assay; FBS, fetal bovine serum; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; HSC, hepatic stellate cells; LDH, lactate dehydrogenase; NF-κB, nuclear factor-κB; RPA, RNase protection assay; α-SMA, α-smooth muscle actin; Tβ-RII, type II TGF-β receptor; TGF-β, transforming growth factor-β; TUNEL, terminal transferase deoxytidyl uridine end labelling.
- The Biochemical Society, London ©2002