Metabolic function of TIR-domain-containing adaptor-inducing interferon-[beta] (TRIF) in diet-induced obesity

Abstract

The family of toll-like receptors (TLRs) is one of the key pattern-recognition receptors in regulating innate immunity and plays a crucial role for host defending against microbial infection. By inducing inflammatory response upon recognizing ligands from microbial components or products, TLRs participate in the pathophysiology of various metabolic and cardiovascular diseases. Non-alcoholic fatty liver disease is a spectrum of disease ranging from hepatic steatosis to steatohepatitis. Hepatic steatosis is the first stage of non-alcoholic fatty liver disease and defined clinically as the fat content in liver exceeds 5% of the total liver weight. Activation of TLRs has been shown to aggravate hepatic steatosis through increasing inflammatory cytokines. Previous studies mainly focused on the role of TLRs in immune cells, and the functions of TLRs in metabolic cells such as hepatocytes are far less explored. In this study it is aimed to investigate the metabolic function of one of their downstream cytosolic adaptors, TIR-domain-containing adapter-inducing interferon-β (TRIF), in hepatocytes. Trif-/- mice fed a high fat diet for 10 weeks presented worsened metabolic phenotypes compared with wild type control, including elevated hepatic total triglyceride and total cholesterol levels, increased fasting blood glucose level and enhanced serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) activities. The increased lipid accumulation in the liver of trif-/- mice was independent of myeloid cells, but was due to the upregulation of stearoyl-CoA-desarase-1 (SCD1), which is the rate-limiting enzyme in triglyceride synthesis in hepatocytes. Activation of TRIF pathway by poly-I:C could inhibit palmitic acid- or high fat diet-induced SCD1 expression, subsequently decreasing triglyceride contents in hepatocytes. The in vitro data showed that TRIF-induced suppression of SCD1 was mediated by interferon regulatory factor 3 (IRF3), which is one of the downstream transcription factors of TRIF. This suppression effect was blocked after mutating IRF3 binding site on scd1 promoter, suggesting that IRF3 acted as a direct suppressor on scd1 transcription. In summary, TRIF participates in lipogenesis regulation in hepatocytes through suppressing SCD1 expression. This study can provide an additional understanding of the metabolic function of TRIF in hepatocytes.