(—)-Epigallocatechin-3-gallate suppresses hepatic preneoplastic lesions developed in a novel rat model of non-alcoholic steatohepatitis

Abstract

PurposeNon-alcoholic fatty liver disease (NAFLD) ranges from simple steatosis to non-alcoholic steatohepatitis (NASH). NASH, which is accompanied by increased oxidative stress and inflammation in the liver, is associated with hepatic carcinogenesis. Green tea catechins (GTCs) possess anti-oxidant, anti-inflammatory, and cancer-preventive properties. In this study, we investigated whether (-)-epigallocatechin-3-gallate (EGCG), a major component of GTCs, inhibits NAFLD/NASH-related liver tumorigenesis.MethodsMale 8-week-old Sprague–Dawley (SD) rats were administered a single intraperitoneal injection of a hepatic carcinogen diethylnitrosamine (DEN, 30 mg/kg body weight) and then fed a high-fat diet (HFD) for 7 weeks. The rats were also provided tap water containing 0.01% or 0.1% EGCG during the experiment.ResultsAt sacrifice, the livers of SD rats treated with DEN and HFD exhibited marked development of glutathione S-transferase placental form (GST-P)-positive foci, a hepatic preneoplastic lesion, and this was associated with hepatic steatosis, oxidative stress and inflammation, and hepatocyte proliferation. EGCG administration, however, inhibited the development of GST-P-positive foci by decreasing hepatic triglyceride content, reducing hepatic fibrosis, lowering oxidative stress, attenuating inflammation, and inhibiting excessive hepatocyte proliferation in DEN- and HFD-treated SD rats. These findings suggest that the experimental model of SD rats treated with HFD and DEN, in which histopathological and pathophysiological characteristics of NASH and the development of hepatic premalignant lesions were observed, might facilitate the evaluation of liver tumorigenesis associated with NAFLD/NASH.ConclusionsAdministering EGCG, a GTC, might serve as an effective chemoprevention modality for NAFLD/NASH-related liver tumorigenesis.

Potential Biological Effects of (‐)‐Epigallocatechin‐3‐gallate on the Treatment of Nonalcoholic Fatty Liver Disease

“…Oxidative stress, chronic inflammation, and numerous pathophysiological mechanisms are critically involved in NAFLD/NASH‐related liver tumorigenesis. Three in vivo studies conducted by a research group from Japan demonstrated that EGCG might be able to prevent NAFLD‐related liver tumorigenesis. In 2011, this research group reported that EGCG (0.1%, for 34 weeks) significantly inhibited the development of liver cell adenomas in the diethylnitrosamine (DEN)‐induced liver tumorigenesis models by inhibiting the phosphorylation of IGF‐1R and related downstream signaling pathways, including the mitogen‐activated protein kinase (MAPK)/ERK and PI3K/Akt pathways, which contribute to the development of HCC.…”

Non-alcoholic steatohepatitis-related liver tumorigenesis is suppressed in mice lacking hepatic retinoid storage

“…Frozen tissue sections were also prepared for ORO staining. Immunohistochemistry was performed using antibodies specific for α-SMA (Abcam, Cambridge, UK), 4-HNE (NIKKEN SEIL, Shizuoka, Japan), 8-OHdG (NIKKEN SEIL) and PCNA (Santa Cruz Biotechnology, Inc., Santa Cruz, CA, USA) [ 47 , 48 ].…”

Nutritional Epigenetics and the Prevention of Hepatocellular Carcinoma with Bioactive Food Constituents

“…treatment of male Fischer 344 rats undergoing DENinduced hepatocarcinogenesis during the initiation and/ or promotion with EGCG significantly decreased the number and reduced area of preneoplastic GSTP-positive foci in the liver. In later studies, Sumi et al (130) and Kochi et al (131), using two different models of NASH-associated liver carcinogenesis in rats, demonstrated that EGCG suppressed the formation of preneoplastic lesions in livers, and Ding et al (132) showed that EGCG treatment attenuated the development of NASH in mice. Additionally, several studies have demonstrated that EGCG is capable of inhibiting the entry and replication of HCV and HBC into hepatocytes (133)(134)(135).…”