Green tea extract treatment reduces NFκB activation in mice with diet-induced nonalcoholic steatohepatitis by lowering TNFR1 and TLR4 expression and ligand availability.

NFκB-mediated inflammation contributes to liver injury during nonalcoholic steatohepatitis (NASH). We hypothesized that antiinflammatory activities of green tea extract (GTE) during NASH would lower tumor necrosis factor receptor-1 (TNFR1)- and Toll-like receptor-4 (TLR4)-mediated NFκB activation. Male C57BL6/J mice (6 weeks old) were fed a low-fat (LF) or high-fat (HF) diet for 12 weeks to induce NASH. They were then randomized to continue on these diets supplemented with 0 or 2% GTE (n=10/group) for an additional 8 weeks prior to evaluating NASH, NFκB inflammation and TNFR1 and TLR4 receptor complexes and their respective ligands, TNFα and endotoxin. HF feeding increased (P<.05) serum alanine aminotransferase (ALT) activity and histological evidence of NASH compared with LF controls. HF-mediated increases in NFκB p65 phosphorylation were also accompanied by increased serum TNFα and endotoxin concentrations, mRNA expression of hepatic TNFR1 and TLR4 and MyD88 protein levels. GTE in LF mice had no effect (P>.05) on liver histology or inflammatory responses. However, GTE in HF mice decreased biochemical and histological parameters of NASH and lowered hepatic p65 phosphorylation in association with decreased serum TNFα, mRNA expression of TNFR1 and TLR4 and MyD88 protein. GTE in HF-fed mice also lowered serum endotoxin and up-regulated mRNA expression of duodenal occludin and zonula occluden-1 and ileal occludin and claudin-1 that were otherwise lowered in expression by HF feeding. These data suggest that dietary GTE treatment reduces hepatic inflammation in NASH by decreasing proinflammatory signaling through TNFR1 and TLR4 that otherwise increases NFκB activation and liver injury.

Green tea extract provides extensive Nrf2-independent protection against lipid accumulation and NFκB pro- inflammatory responses during nonalcoholic steatohepatitis in mice fed a high-fat diet.

SCOPE: Green tea extract (GTE) reduces liver steatosis and inflammation during nonalcoholic steatohepatitis (NASH). We hypothesized GTE would mitigate NASH in a nuclear factor erythroid-2-related-factor-2 (Nrf2)-dependent manner in a high fat (HF) induced model. METHODS AND RESULTS: Nrf2-null and wild-type (WT) mice were fed an HF diet containing 0 or 2% GTE for eight weeks prior to assessing parameters of NASH. Compared to WT mice, Nrf2-null mice had increased serum alanine aminotransferase, hepatic triglyceride, expression of free fatty acid uptake and lipogenic genes, malondialdehyde and NFκB phosphorylation and expression of pro-inflammatory genes. In WT mice, GTE increased Nrf2 and NADPH:quinone oxidoreductase-1 mRNA, and lowered hepatic steatosis, lipid uptake and lipogenic gene expression, malondialdehyde, and NFκB-dependent inflammation. In Nrf2-null mice, GTE lowered NFκB phosphorylation and TNF-α and MCP1 mRNA to levels observed in WT mice fed GTE whereas hepatic triglyceride and lipogenic genes were lowered only to those of WT mice fed no GTE. Malondialdehyde was lowered in Nrf2-null mice fed GTE, but not to levels of WT mice, and without improving the hepatic antioxidants α-tocopherol, ascorbic acid and uric acid. CONCLUSION: Nrf2 deficiency exacerbates NASH whereas anti-inflammatory and hypolipidemic activities of GTE likely occur largely independent of Nrf2 signaling.