Melanoma differentiation—Associated gene 5 protects against NASH in mice

Abstract Background and Aims NASH is a complicated disease characterized by hepatocyte steatosis, inflammation infiltration, and liver fibrosis. Accumulating evidence suggests that the innate immunity plays a key role in NASH progression. Here, we aimed to reveal the role of melanoma differentiation–associated gene 5 (MDA5, also known as Ifih1), a conventional innate immune regulator following viral infection, in the progression of NASH and investigate its underlying mechanism. Approach and Results We first examined the expression of MDA5 and found that MDA5 was markedly down‐regulated in the livers with NASH in human individuals and mice models. MDA5 overexpression significantly inhibits the free fatty acid–induced lipid accumulation and inflammation in hepatocyte in vitro, whereas MDA5 knockdown promotes hepatocyte lipotoxicity. Using hepatocyte‐specific Mda5 gene knockout and transgenic mice, we found that diet‐induced hepatic steatosis, inflammation, and liver fibrosis were markedly exacerbated by Mda5 deficiency but suppressed by Mda5 overexpression. Mechanistically, we found that the activation of apoptosis signal‐regulating kinase 1 (ASK1)–mitogen‐activated protein kinase pathway was significantly inhibited by MDA5 but enhanced by MDA5 deletion. We further validated that MDA5 directly interacted with ASK1 and suppressed its N‐terminal dimerization. Importantly, blockage of ASK1 with adenovirus‐expressing dominant negative ASK1 obviously reversed the lipid accumulation and ASK1 pathway activation when Mda5 was knocked out. Conclusions These data indicate that MDA5 is an essential suppressor in NASH. The findings support MDA5 as a regulator of ASK1 and a promising therapeutic target for NASH.