Abstract
Systemic metabolic syndrome significantly increases the risk of morbidity and mortality in patients with non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH). However, no effective therapeutic strategies are available, practically because our understanding of its complicated pathogenesis is poor. Here we identify the tripartite motif-containing protein 31 (Trim31) as an endogenous inhibitor of rhomboid 5 homolog 2 (Rhbdf2), and we further determine that Trim31 directly binds to Rhbdf2 and facilitates its proteasomal degradation. Hepatocyte-specific Trim31 ablation facilitates NAFLD-associated phenotypes in mice. Inversely, transgenic or ex vivo gene therapy-mediated Trim31 gain-of-function in mice with NAFLD phenotypes virtually alleviates severe deterioration and progression of steatohepatitis. The current findings suggest that Trim31 is an endogenous inhibitor of Rhbdf2 and downstream cascades in the pathogenic process of steatohepatitis and that it may serve as a feasible therapeutical target for the treatment of NAFLD/NASH and associated metabolic disorders.
Highlights
Systemic metabolic syndrome significantly increases the risk of morbidity and mortality in patients with non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH)
The severity of NAFLD ranges from simple steatosis to hepatocyte injury with malignant transformation and necrotizing inflammatory alterations characterized as nonalcoholic steatohepatitis (NASH), which renders patients more susceptible to liver fibrosis and hepatocellular carcinoma[6,7]
We revealed that Trim[31] mitigates genetically and high-energy diet-triggered insulin resistance, liver steatosis, inflammation, and hepatic fibrosis by promoting degradation of Rhbdf[2] by K48-linked polyubiquitination, which results in suppression of Rhbdf2-MAP3K7 signaling and downstream events
Summary
Systemic metabolic syndrome significantly increases the risk of morbidity and mortality in patients with non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH). The current findings suggest that Trim[31] is an endogenous inhibitor of Rhbdf[2] and downstream cascades in the pathogenic process of steatohepatitis and that it may serve as a feasible therapeutical target for the treatment of NAFLD/NASH and associated metabolic disorders. A previous study speculated that the half-life of Rhbdf[2] is significantly prolonged in the presence of the proteasomal inhibitor MG-132, further indicating that there may be K48-linked ubiquitination sites in the cytoplasmic domain, and proteasomal degradation[17] It is still unknown whether there are certain regulatory factors that control the ubiquitination of Rhbdf[2] and Rhbdf2-mediated pathogenesis of NAFLD/NASH. Trim31-mediated invasion and metastasis in colorectal cancer are enhanced by regulating of NF-κB signaling-associated chronic inflammation[23] These seemingly contradictory findings revealed that Trim[31] virtually has completely distinct functions in different pathological processes. These studies have prompted us to explore the molecular mechanism of Trim[31] in depth
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