Key result
Hepatocyte TRUSS promotes NAFLD and metabolic disorders by promoting the ubiquitination and degradation of IκBα, leading to aberrant activation of NF-κB.
Why the study?
Does TRUSS promote NAFLD development by regulating IκBα degradation and NF-κB activation in mice?
Does TRUSS promote NAFLD development by regulating IκBα degradation and NF-κB activation in mice?
Hepatocyte TRUSS promotes NAFLD and metabolic disorders by activating NF-κB through the ubiquitination and degradation of IκBα, suggesting TRUSS as a potential therapeutic target.
Should not change NAFLD practice; hypothesis-generating for TRUSS as therapeutic target.
There is no effective treatment method for nonalcoholic fatty liver disease (NAFLD), the most common liver disease. The exact mechanism underlying the pathogenesis of NAFLD remains to be elucidated. Here, we report that tumor necrosis factor receptor–associated ubiquitous scaffolding and signaling protein (TRUSS) acts as a positive regulator of NAFLD and in a variety of metabolic disorders. TRUSS expression was increased in the human liver specimens with NAFLD or nonalcoholic steatohepatitis, and in the livers of high‐fat diet (HFD)‐induced and genetically obese mice. Conditional knockout of TRUSS in hepatocytes significantly ameliorated hepatic steatosis, insulin resistance, glucose intolerance, and inflammatory responses in mice after HFD challenge or in spontaneous obese mice with normal chow feeding. All of these HFD‐induced pathological phenotypes were exacerbated in mice overexpressing TRUSS in hepatocytes. We show that TRUSS physically interacts with the inhibitor of nuclear factor κB α (IκB α ) and promotes the ubiquitination and degradation of IκB α , which leads to aberrant activation of nuclear factor κB (NF‐κB). Overexpressing IκB α S32A/S36A , a phosphorylation‐resistant mutant of IκB α , in the hepatocyte‐specific TRUSS overexpressing mice almost abolished HFD‐induced NAFLD and metabolic disorders. Conclusion : Hepatocyte TRUSS promotes pathological stimuli‐induced NAFLD and metabolic disorders, through activation of NF‐κB by promoting ubiquitination and degradation of IκB α . Our findings may provide a strategy for the prevention and treatment of NAFLD by targeting TRUSS.
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Yu et al. (2018) studied Nonalcoholic fatty liver disease (NAFLD). TRUSS knockout or overexpression vs. Control mice was evaluated on Hepatic steatosis, insulin resistance, glucose intolerance, and inflammatory responses. Hepatocyte TRUSS promotes NAFLD and metabolic disorders by promoting the ubiquitination and degradation of IκBα, leading to aberrant activation of NF-κB.
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