Bax Inhibitor-1 protects from Non-Alcoholic Steatohepatitis by limiting IRE1α signaling

Abstract

Endoplasmic reticulum (ER) stress is activated in non-alcoholic fatty liver disease (NAFLD), raising the possibility that ER stress-dependent metabolic dysfunction, inflammation and cell death underlie the transition from steatosis to steatohepatitis (NASH). Bax inhibitor-1 (BI-1), a negative regulator of the ER stress sensor IRE1α, has yet to be explored in NAFLD as a hepatoprotective agent. We hypothesized that the genetic ablation of BI-1 would render the liver vulnerable to NASH due to unrestrained IRE1α signaling. ER stress was induced in wild-type and BI-1^-/- mice acutely by tunicamycin injection (1 mg/kg) or chronically by high-fat diet (HFD) feeding to determine the NAFLD phenotype. Livers of tunicamycin-treated BI-1^-/- mice showed IRE1α-dependent NLRP3 inflammasome activation, hepatocyte death, fibrosis and dysregulated lipid homeostasis that led to liver failure within a week. The analysis of human NAFLD liver biopsies revealed BI-1 downregulation parallel to the upregulation of IRE1α endoribonuclease (RNase) signaling. In HFD-fed BI-1^-/- mice that presented NASH and type-2 diabetes, exaggerated hepatic IRE1α, XBP1 and CHOP expression was linked to activated NLRP3 inflammasome and caspase-1/-11. Rises in IL-1β, IL-6, MCP1, CXCL1 and ALT/AST levels revealed significant inflammation and injury, respectively. The pharmacological inhibition of IRE1α RNase activity with the small molecules STF-083010 or 4µ8c was evaluated in HFD-induced NAFLD. In BI-1^-/- mice, either treatment effectively counteracted IRE1α RNase activity, improving glucose tolerance and rescuing from NASH. The hepatocyte-specific role of IRE1α RNase activity in mediating NLRP3 inflammasome activation and cell death was confirmed in primary mouse hepatocytes by IRE1α axis knockdown or its inhibition with STF-083010 or 4µ8c. Conclusion: Targeting IRE1α-dependent NLRP3 inflammasome signaling with pharmacological agents or via BI-1 may represent a tangible therapeutic strategy for NASH. This article is protected by copyright. All rights reserved.

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