Epigallocatechin 3-gallate ameliorates bile duct ligation induced liver injury in mice by modulation of mitochondrial oxidative stress and inflammation

Kezhen Shen; Xiaowen Feng; Rong Su; Haiyang Xie; Lin Zhou; Shusen Zheng

doi:10.1371/journal.pone.0126278

Epigallocatechin 3-gallate ameliorates bile duct ligation induced liver injury in mice by modulation of mitochondrial oxidative stress and inflammation

PLoS One. 2015 May 8;10(5):e0126278. doi: 10.1371/journal.pone.0126278. eCollection 2015.

Authors

Kezhen Shen¹, Xiaowen Feng¹, Rong Su¹, Haiyang Xie¹, Lin Zhou¹, Shusen Zheng²

Affiliations

¹ Key Laboratory of Combined Multi-organ Transplantation, Ministry of Public Health, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, China; Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, China.
² Key Laboratory of Combined Multi-organ Transplantation, Ministry of Public Health, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, China; Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, China; Division of Hepatobiliary and Pancreatic Surgery, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.

Abstract

Cholestatic liver fibrosis was achieved by bile duct ligation (BDL) in mice. Liver injury associated with BDL for 15 days included significant reactive oxygen/nitrogen species generation, liver inflammation, cell death and fibrosis. Administration of Epigallocatechin 3-Gallate (EGCG) in animals reduced liver fibrosis involving parenchymal cells in BDL model. EGCG attenuated BDL-induced gene expression of pro-fibrotic markers (Collagen, Fibronectin, alpha 2 smooth muscle actin or SMA and connective tissue growth factor or CTGF), mitochondrial oxidative stress, cell death marker (DNA fragmentation and PARP activity), NFκB activity and pro-inflammatory cytokines (TNFα, MIP1α, IL1β, and MIP2). EGCG also improved BDL induced damages of mitochondrial electron transport chain complexes and antioxidant defense enzymes such as glutathione peroxidase and manganese superoxide dismutase. EGCG also attenuated hydrogen peroxide induced cell death in hepatocytes in vitro and alleviate stellate cells mediated fibrosis through TIMP1, SMA, Collagen 1 and Fibronectin in vitro. In conclusion, the reactive oxygen/nitrogen species generated from mitochondria plays critical pathogenetic role in the progression of liver inflammation and fibrosis and this study indicate that EGCG might be beneficial for reducing liver inflammation and fibrosis.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Bile Ducts, Intrahepatic / drug effects
Bile Ducts, Intrahepatic / injuries*
Catechin / administration & dosage
Catechin / analogs & derivatives*
Catechin / pharmacology
Cell Death / drug effects
Cholestasis / complications
Cholestasis / drug therapy*
Cholestasis / etiology
Cytokines / metabolism
Disease Models, Animal
Gene Expression Regulation / drug effects
Hepatic Stellate Cells / drug effects
Hepatic Stellate Cells / pathology
Hepatocytes / drug effects
Inflammation / drug therapy*
Inflammation / etiology
Liver Cirrhosis / drug therapy*
Liver Cirrhosis / etiology
Mice
Mitochondria / drug effects
NF-kappa B / metabolism
Oxidative Stress / drug effects*

Substances

Cytokines
NF-kappa B
Catechin
epigallocatechin gallate

Grants and funding

This work was supported by grants from National S&T Major Project (No.2012ZX10002-017), Science and Technology Department of Zhejiang Province(no. 2013C37053), Education Department of Zhejiang Province (Y201326715,Y200908541). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.