Altered Inflammatory Pathway but Unaffected Liver Fibrosis in Mouse Models of Nonalcoholic Steatohepatitis Involving Interleukin-1 Receptor-Associated Kinase 1 Knockout

BACKGROUND: Interleukin-1 receptor-associated kinases (IRAKs) are crucial mediators in the signaling pathways of Toll-like receptors (TLRs)/IL1Rs. Targeting the IRAK4/IRAK1/TRAF6 axis and its associated pathway has therapeutic benefits in liver fibrosis. However, the function of IRAK1 itself in the development of liver fibrosis remains unknown. MATERIAL/METHODS: Irak1 global knockout (KO) mice were generated to study the functional role of Irak1 in liver fibrosis. Male Irak1 knockout and control mice were challenged with chronic carbon tetrachloride (CCl(4)) or fed a methionine- and choline-deficient diet (MCDD) to generate models of nonalcoholic steatohepatitis (NASH). Liver inflammation and collagen deposition were assessed by histological examination, quantitative real-time PCR (qRT-PCR), and western blotting of hepatic tissues. RESULTS: The mRNA expression of the downstream inflammatory gene Il1β was significantly lower in Irak1-KO than in control mice. Irak1 ablation had little effect on inflammatory cell infiltration into livers of mice with NASH. Collagen deposition and the expression of genes related to fibrogenesis were similar in the livers of Irak1-KO and control mice exposed to CCl(4) and MCDD. The loss of Irak1 did not affect lipid or glucose metabolism in these experimental models of steatohepatitis. CONCLUSIONS: Irak1 knockout reduced the expression of inflammatory genes but had no effect on hepatic fibrogenesis. The Irak1-related pathway may regulate liver fibrosis via other pathways or be compensated for by other factors.