USP18 protects against hepatic steatosis and insulin resistance via its DUB activity

Abstract

Non-alcoholic fatty liver disease (NAFLD) is characterized by hepatic steatosis, impaired insulin sensitivity and chronic low-grade inflammation. However, the pathogenic mechanism of NAFLD is poorly understood, which hinders the exploration of possible treatments. Here, we first report that ubiquitin-specific protease 18 (USP18), a member of the deubiquitinating (DUB) enzyme family, plays regulatory roles in NAFLD progression. The expression of USP18 was down-regulated in the livers of non-alcoholic steatohepatitis (NASH) patients and high-fat diet (HFD) induced or genetically obese mice. When challenged with HFD, hepatocyte-specific USP18 transgenic (HTG) mice exhibited improved lipid metabolism and insulin sensitivity, whereas mice knocked out of USP18 expression (HKO) showed adverse trends regarding hepatic steatosis and glucose metabolic disorders. Furthermore, the concomitant inflammatory response was suppressed in USP18-HTG mice and promoted in USP18-HKO mice treated with HFD. Mechanistically, hepatocyte USP18 ameliorates hepatic steatosis by interacting with and deubiquitinating TGFβ-activated kinase 1 (TAK1), which inhibits TAK1 activation and subsequently suppresses the downstream JNK and NF-κB signaling pathways. This is further validated by alleviated steatotic phenotypes and highly activated insulin signaling in HFD-fed USP18-HKO mice administered with TAK1 inhibitor. The therapeutic effect of USP18 on NAFLD relies on its deubiquitinating activity because HFD-fed mice injected with active-site mutant USP18 failed to inhibit hepatic steatosis.

Conclusion: USP18 associates with and deubiquitinates TAK1 to protect against hepatic steatosis, insulin resistance and the inflammatory response. This article is protected by copyright. All rights reserved.

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