Catechin‐Rich Green Tea Extract and the Loss‐of‐TLR4 Signaling Differentially Alter the Hepatic Metabolome in Mice with Nonalcoholic Steatohepatitis

Scope Catechin-rich green tea extract (GTE) limits inflammation in nonalcoholic steatohepatitis (NASH) consistent with a Toll-like receptor 4 (TLR4)-dependent mechanism. Our hypothesis was that GTE supplementation during NASH would shift the hepatic metabolome similar to that attributed to the loss-of-TLR4 signaling. Methods and results Wild-type (WT) and loss-of-function TLR4-mutant (TLR4mut ) mice were fed a high-fat diet containing 0% or 2% GTE for 8 weeks prior to performing untargeted mass spectrometry-based metabolomics on liver tissue. The loss-of-TLR4 signaling and GTE shifted the hepatic metabolome away from that of WT mice. However, relatively few metabolites were altered by GTE in WT mice to the same extent as the loss-of-TLR4 signaling in TLR4mut mice. GTE increased acetyl-CoA precursors and spermidine to a greater extent than the loss-of-TLR4 signaling. Select metabolites associated with thiol metabolism were similarly affected by GTE and the loss-of-TLR4 signaling. Glycerophospholipid catabolites were decreased by GTE, but were unaffected in TLR4mut mice. Conversely, the loss-of-TLR4 signaling but not GTE increased several bile acid metabolites. Conclusion GTE limitedly alters the hepatic metabolome consistent with a TLR4-dependent mechanism. This suggests that the anti-inflammatory activities of GTE and loss-of-TLR4 signaling that regulate hepatic metabolism to abrogate NASH are likely due to distinct mechanisms. This article is protected by copyright. All rights reserved.