Down Regulated XIAP Promotes Long-Term High Fat Diet-Stimulated NAFLD Through NLRP3 Inflammasome Activation and Oxidative Stress Signaling

Abstract

Increasing evidence indicates that prolonged fat-rich diet (HFD) ingestion is a predisposing factor for metabolic disorderassociated system inflammation and oxidative stress injury, which contributes to the occurrence of non-alcoholic fatty liver disease (NAFLD). NACHT, LRR and PYD domains-containing protein 3 (NLRP3)-mediated inflammatory infiltration was determined to participate in NAFLD. Xlinked inhibitor of apoptosis protein (XIAP) was recently confirmed as an essential regulator for apoptosis in cells. However, the role of XIAP in HFD-induced NAFLD is still not understood. Here, XIAP was characterized with respect to HFD-induced NLRP3 inflammasome activation and reactive oxygen species (ROS) generation in vivo and palmitate (PA)-treated cells in vitro. After HFD administration, hepatic injury was confirmed via histological assessment (grading and staging of NAFLD) and biochemical parameters, oxidative stress, and reduced antioxidant activity. Upregulated hepatic dysfunction were further indicated by elevated dyslipidemia, lipid accumulation, and decreased fatty acid β-oxidationassociated gene expression. Moreover, in the absence of XIAP, NLRP3 signaling activated by HFD-triggered oxidative stress was upregulated, accompanied by reduction in antioxidants including HO-1, NQO-1, GST, SOD and Nrf2 activity. The detrimental effects of XIAP blocking on hepatic steatosis and related pathologies were also confirmed in PA-treated mouse liver cells. In contrast, overexpression of XIAP by transfection in vitro restrained PA-stimulated hepatic steatosis by suppression of oxidative stress, NLRP3 related inflammatory response, and impairment of Nrf2 activity, further alleviating abnormal metabolic disorder associated NAFLD. Taken together, the present study helped to elucidate how HFDinduced hepatic steatosis was regulated by XIAP, possibly via the inhibition of NLRP3 signaling and oxidative stress injury. Funding Statement: This work was supported by National Natural Science Foundation of China (NSFC Grant number: 81703527); Chongqing Research Program of Basic Research and Frontier Technology (Grant number: cstc2017jcyjAX0356, cstc2018jcyjA3686, cstc2018jcyjA1472 and cstc2018jcyjA3533); 2018 Chongqing College Students' Innovation and Entrepreneurship Training Project (Grant number: 201814388021 and 201814388022); School-level Research Program of Chongqing University of Education (Grant number: KY201710B and 17GZKP01) and Advanced Programs of Post-doctor of Chongqing (Grant number: 2017LY39). Declaration of Interests: The authors declare that there are no conflicts of interest regarding the publication of this manuscript. Ethics Approval Statement: All study protocols associating with animals were approved by the Institutional Animal Care and Use Committee in Chongqing Key Laboratory of Medicinal Resources in the Three Gorges Reservoir Region, School of Biological and Chemical Engineering, Chongqing University of Education.