Green Tea Extract Protects Against Hepatic NFκB Activation Along The Gut‐Liver Axis in Diet‐Induced Obese Mice With Nonalcoholic Steatohepatitis By Reducing Endotoxin and TLR4/MyD88 Signaling

Abstract

Green tea extract (GTE) reduces NFκB‐mediated inflammation during nonalcoholic steatohepatitis (NASH). We hypothesized that its antiinflammatory activities would be mediated along the gut‐liver axis 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) GTE for 8 wk before assessing NASH, NFκB‐mediated inflammation, TLR4 adaptor proteins [myeloid differentiation 88 (MyD88) and TIR‐domain‐containing adapter‐inducing interferon‐β (TRIF)], circulating endotoxin, and intestinal tight junction proteins. In WT mice, phosphorylation of the NFκB p65 subunit and NFκB‐dependent gene expression (MCP‐1, iNOS, MPO) were lower in those provided GTE, and were not different from the lowered levels in TLR4m mice regardless of GTE. Compared with WT controls, TLR4m mice had lower TLR4 mRNA expression, and its expression was lowered by GTE in both genotypes. Protein expression of TRIF, which mediates MyD88‐independent TLR4 signaling, was unaffected by genotype and GTE. In contrast, MyD88 expression was lower in mice fed GTE regardless of genotype. Serum endotoxin was not exacerbated in TLR4m mice, but was lowered by GTE in both genotypes. Similarly, duodenal and jejunal claudin‐1 (CLDN‐1) mRNA expression were not affected in TLR4m mice, but GTE increased their expression in both genotypes. Serum endotoxin was inversely correlated with duodenal and jejunal CLDN‐1 (rp= −0.58 to −0.43, p<0.05), and positively correlated with expression levels of TLR4 and phosphorylated‐p65 (rp= 0.46–0.57; p<0.05). Thus, GTE protects against inflammation during NASH, likely by limiting gut‐derived endotoxin translocation and TLR4/MyD88‐dependent NFκB activation.Support or Funding InformationSupported by USDA‐NIFA.