Green tea extract lowers NFκB‐mediated inflammation during nonalcoholic steatohepatitis in mice fed a high‐fat diet consistent with reduced Toll‐like receptor‐4 signaling

Abstract

Green tea extract (GTE) reduces NFκB‐mediated inflammation and oxidative stress during nonalcoholic steatohepatitis (NASH). We hypothesized that its antiinflammatory activities that limit oxidative stress and liver steatosis would be mediated in a Toll‐like receptor‐4 (TLR4)‐ dependent manner. Wild‐type (WT) and loss‐of‐function TLR4‐mutant (TLR4m) mice were fed a high‐fat diet containing 0 or 2% (w/w) powdered GTE for 8 wk before assessing hepatic steatosis, oxidative stress, and NFκB‐mediated inflammation. TLR4m mice had lower (P<0.05) body mass compared to WT mice, but similarly high adipose mass, whereas body mass and adiposity were lowered by GTE regardless of genotype. GTE in WT mice reduced hepatic TLR4 and MCP‐1 mRNA, and protein levels of the phosphorylated‐p65 NFκB subunit, which were also lowered in TLR4m mice regardless of GTE. Oxidized:reduced glutathione and malondialdehyde were lowered by GTE in WT mice and similarly lowered in TLR4m mice regardless of GTE. Relative to WT mice, histological evidence of liver steatosis, hepatic triglyceride, and serum alanine aminotransferase were also lowered in WT mice fed GTE and these were similarly lowered in TLR4m mice regardless of GTE. However, GTE lowered lipogenic gene expression regardless of genotype, but their expression in TLR4 controls was unaffected compared to WT controls. TLR4m mice had reduced insulin resistance compared to WT mice, but GTE in WT mice lowered it to a greater extent by more substantially reducing fasting glucose. These findings suggest that GTE limits NFκB‐mediated inflammatory responses leading to liver steatosis and oxidative stress during NASH, consistent with a mechanism of reduced pro‐inflammatory signaling through TLR4/NFκB.Support or Funding InformationSupported by USDA‐NIFA and Ohio Agricultural Research and Development Center