TRUSS Exacerbates NAFLD Development by Promoting IκBα Degradation in Mice

Abstract

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 (IκBα) and promotes the ubiquitination and degradation of IκBα, which leads to aberrant activation of nuclear factor κB (NF-κB). Overexpressing IκBα , a phosphorylation-resistant mutant of IκBα, 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 IκBα. Our findings may provide a strategy for the prevention and treatment of NAFLD by targeting TRUSS.

Serum amyloid A1 exacerbates hepatic steatosis via TLR4-mediated NF-κB signaling pathway

“…However, the increased AKT phosphorylation was accompanied with the unaltered sterol regulatory element binding transcription factor-1C (SREBP-1C) expression in SAA1-deficient murine liver. Consistent observations are also reported in other inflammation-driven NAFLD models, in which the inflammatory mediators have impact to enhance lipid synthesis [ 35 , 36 ]. The increase in NEFA and suppression of its metabolism in hepatocytes induced by SAA1 may promote the development of NASH.…”

Myeloid-derived growth factor alleviates non-alcoholic fatty liver disease alleviates in a manner involving IKKβ/NF-κB signaling

“…Interestingly, our recent study demonstrated that myeloid-derived growth factor (MYDGF), a protein secreted from bone marrow-derived monocytes and macrophages [ 10 ], improved IR and glucose-lipid metabolic profiles in diabetic mice [ 11 ]. Metabolic disorders have also been shown to be closely associated with NAFLD [ 12 , 13 ]. Therefore, in this study, we first aimed to ascertain whether MYDGF can modulate NAFLD and the possible underlying mechanisms, before exploring whether MYDGF serves as a factor involved in the crosstalk between bone marrow and liver that regulates liver fat metabolism.…”

TRP (transient receptor potential) ion channel family: structures, biological functions and therapeutic interventions for diseases

“…These findings suggest that TRPC3 and TRPC6 are unlikely to be implicated in liver dysfunction and fibrosis in NAFLD mouse models. 328 No effective therapy is available for NAFLD, and its exact pathogenesis remains to be elucidated. All these data indicate that TRP channels may be an interesting target for drug development for the treatment of NAFLD.…”