TRIF Differentially Regulates Hepatic Steatosis and Inflammation/Fibrosis in Mice

Translocated intestine-derived lipopolysaccharide stimulates Toll-like receptor 4 expressed in different liver cells that have distinct roles in the development of nonalcoholic steatohepatitis. The Toll-like receptor 4-mediated TIR-domain containing adaptor-inducing interferon-beta pathway promotes liver steatosis, but inhibits inflammation and fibrosis in nonalcoholic steatohepatitis. BACKGROUND & AIMS: Toll-like receptor 4 (TLR4) signaling is activated through 2 adaptor proteins: MyD88 and TIR-domain containing adaptor-inducing interferon-b (TRIF). TLR4 and MyD88 are crucial in nonalcoholic steatohepatitis (NASH) and fibrosis. However, the role of TRIF in TLR4-mediated NASH and fibrosis has been elusive. This study investigated the differential roles of TRIF in hepatic steatosis and inflammation/fibrosis. METHODS: A choline-deficient amino acid defined (CDAA) diet was used for the mouse NASH model. On this diet, the mice develop hepatic steatosis, inflammation, and fibrosis. TLR4 wild-type and TLR4(-/-) bone marrow chimeric mice and TRIF-/- mice were fed CDAA or a control diet for 22 weeks. Hepatic steatosis, inflammation, and fibrosis were examined. RESULTS: In the CDAA diet-induced NASH, the mice with wildtype bone marrow had higher alanine aminotransferase and hepatic tumor necrosis factor levels than the mice with TLR4(-/-) bone marrow. The nonalcoholic fatty liver disease activity score showed that both wild-type and TLR4-/-bone marrow chimeras had reduced hepatic steatosis, and that both types of chimeras had similar levels of inflammation and hepatocyte ballooning to whole-body wild-type mice. Notably, wild-type recipients showed more liver fibrosis than TLR4(-/-) recipients. Although TRIF-/- mice showed reduced hepatic steatosis, these mice showed more liver injury, inflammation, and fibrosis than wildtype mice. TRIF-/- stellate cells and hepatocytes produced more C-X-C motif chemokine ligand 1 (CXCL1) and C-C motif chemokine ligand than wild-type cells in response to lipopolysaccharide. Consistently, TRIF-/- mice showed increased CXCL1 and CCL3 expression along with neutrophil and macrophage infiltration, which promotes liver inflammation and injury. CONCLUSIONS: In TLR4-mediated NASH, different liver cells have distinct roles in hepatic steatosis, inflammation, and fibrosis. TRIF promotes hepatic steatosis but it inhibits injury, inflammation, and fibrosis.