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The antifibrogenic effect of (-)-epigallocatechin gallate results from the induction of de novo synthesis of glutathione in passaged rat hepatic stellate cells.
Lab Invest. 2006 Jul; 86(7):697-709.LI

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-beta) is the most potent fibrogenic cytokine while connective tissue growth factor (CTGF) mediates the production of TGF-beta-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-beta signaling through attenuating oxidative stress. It is found that EGCG interrupts TGF-beta signaling in activated HSC by suppressing gene expression of type I and II TGF-beta receptors. EGCG inhibits CTGF gene expression, leading to the reduction in the abundance of ECM, including alphaI(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-beta signaling and to reduce the abundance of alphaI(I) procollagen in activated HSC in vitro. Taken together, our results demonstrate that the interruption of TGF-beta 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.

Authors+Show Affiliations

Department of Cellular Biology and Anatomy, Louisiana State University Health Sciences Center in Shreveport, Shreveport, LA 71130, USA.No affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

16682975

Citation

Yumei, Fu, et al. "The Antifibrogenic Effect of (-)-epigallocatechin Gallate Results From the Induction of De Novo Synthesis of Glutathione in Passaged Rat Hepatic Stellate Cells." Laboratory Investigation; a Journal of Technical Methods and Pathology, vol. 86, no. 7, 2006, pp. 697-709.
Yumei F, Zhou Y, Zheng S, et al. The antifibrogenic effect of (-)-epigallocatechin gallate results from the induction of de novo synthesis of glutathione in passaged rat hepatic stellate cells. Lab Invest. 2006;86(7):697-709.
Yumei, F., Zhou, Y., Zheng, S., & Chen, A. (2006). The antifibrogenic effect of (-)-epigallocatechin gallate results from the induction of de novo synthesis of glutathione in passaged rat hepatic stellate cells. Laboratory Investigation; a Journal of Technical Methods and Pathology, 86(7), 697-709.
Yumei F, et al. The Antifibrogenic Effect of (-)-epigallocatechin Gallate Results From the Induction of De Novo Synthesis of Glutathione in Passaged Rat Hepatic Stellate Cells. Lab Invest. 2006;86(7):697-709. PubMed PMID: 16682975.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The antifibrogenic effect of (-)-epigallocatechin gallate results from the induction of de novo synthesis of glutathione in passaged rat hepatic stellate cells. AU - Yumei,Fu, AU - Zhou,Yajun, AU - Zheng,Shizhong, AU - Chen,Anping, Y1 - 2006/05/08/ PY - 2006/5/10/pubmed PY - 2006/8/24/medline PY - 2006/5/10/entrez SP - 697 EP - 709 JF - Laboratory investigation; a journal of technical methods and pathology JO - Lab Invest VL - 86 IS - 7 N2 - 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-beta) is the most potent fibrogenic cytokine while connective tissue growth factor (CTGF) mediates the production of TGF-beta-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-beta signaling through attenuating oxidative stress. It is found that EGCG interrupts TGF-beta signaling in activated HSC by suppressing gene expression of type I and II TGF-beta receptors. EGCG inhibits CTGF gene expression, leading to the reduction in the abundance of ECM, including alphaI(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-beta signaling and to reduce the abundance of alphaI(I) procollagen in activated HSC in vitro. Taken together, our results demonstrate that the interruption of TGF-beta 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. SN - 0023-6837 UR - https://www.unboundmedicine.com/medline/citation/16682975/The_antifibrogenic_effect_of_____epigallocatechin_gallate_results_from_the_induction_of_de_novo_synthesis_of_glutathione_in_passaged_rat_hepatic_stellate_cells_ L2 - https://doi.org/10.1038/labinvest.3700425 DB - PRIME DP - Unbound Medicine ER -