Abstract
BackgroundInnate immune dysfunction contributes to the development and progression of nonalcoholic fatty liver disease (NAFLD), however, its pathogenesis is still incompletely understood. Identifying the key innate immune component responsible for the pathogenesis of NAFLD and clarifying the underlying mechanisms may provide therapeutic targets for NAFLD. Recently, F-box- and WD repeat domain-containing 7 (FBXW7) exhibits a regulatory role in hepatic glucose and lipid metabolism. This study aims to investigate whether FBXW7 controls high-mobility group box 1 protein (HMGB1)-mediated innate immune signaling to improve NAFLD and the mechanism underlying this action.MethodsMice were fed a high-fat diet (HFD) for 12 or 20 weeks to establish NAFLD model. Hepatic overexpression or knockdown of FBXW7 was induced by tail-vein injection of recombinant adenovirus. Some Ad-FBXW7-injected mice fed a HFD were injected intraperitoneally with recombinant mouse HMGB1 to confirm the protective role of FBXW7 in NAFLD via inhibition of HMGB1.ResultsFBXW7 improves NAFLD and related metabolic parameters without remarkable influence of body weight and food intake. Moreover, FBXW7 markedly ameliorated hepatic inflammation and insulin resistance in the HFD-fed mice. Furthermore, FBXW7 dramatically attenuated the expression and release of HMGB1 in the livers of HFD-fed mice, which is associated with inhibition of protein kinase R (PKR) signaling. Thereby, FBXW7 restrains Toll-like receptor 4 (TLR4) and receptor for advanced glycation end products (RAGE) signaling in HFD-fed mouse livers. In addition, exogenous HMGB1 treatment abolished FBXW7-mediated inhibition of hepatic inflammation and insulin resistance in HFD-fed mouse livers.ConclusionsOur results demonstrate a protective role of FBXW7 in NAFLD by abating HMGB1-mediated innate immune signaling to suppress inflammation and consequent insulin resistance, suggesting that FBXW7 is a potential target for therapeutic intervention in NAFLD development.
Highlights
Innate immune dysfunction contributes to the development and progression of nonalcoholic fatty liver disease (NAFLD), its pathogenesis is still incompletely understood
This study provides the experimental evidence for the protective role of F-box- and WD repeat domain-containing 7 (FBXW7) against innate immune dysfunction-mediated NAFLD development, as well as the mechanism underlying this action, indicating that FBXW7 is a potential target for therapeutic intervention in NAFLD
Our results showed that the protein levels of FBXW7 were dramatically diminished in the livers of green fluorescent protein (GFP)- injected mice fed a high-fat diet (HFD) compared with ND-fed controls (Fig. 1a), which is consistent with those reports (Tu et al 2012; Zhao et al 2018)
Summary
Innate immune dysfunction contributes to the development and progression of nonalcoholic fatty liver disease (NAFLD), its pathogenesis is still incompletely understood. Liver-specific Fbxw knockout mice exhibit an impaired glucose and lipid homeostasis due to the abolishment of FBXW7-mediated degradation of several protein substrates such as REV-ERBα and hepatokine Fetuin A (Onoyama et al 2011; Zhao et al 2016, 2018). These studies indicate a regulatory role of FBXW7 in metabolic diseases including NAFLD. Whether FBXW7 controls innate immune signaling to modulate NAFLD development and progression has yet to be investigated
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
