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

ScopeGreen 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 resultsNrf2-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 NFB 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 NFB-dependent inflammation. In Nrf2-null mice, GTE lowered NFB phosphorylation and TNF- 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 -tocopherol, ascorbic acid and uric acid. ConclusionNrf2 deficiency exacerbates NASH whereas anti-inflammatory and hypolipidemic activities of GTE likely occur largely independent of Nrf2 signaling.