Bax inhibitor-1 protects from nonalcoholic steatohepatitis by limiting inositol-requiring enzyme 1 alpha signaling in mice
Bax inhibitor-1 protects from nonalcoholic steatohepatitis by limiting inositol-requiring enzyme 1 alpha signaling in mice
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DOI：
10.1002/hep.29847
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发表时间：
2018-08-01
期刊：
影响因子：
13.5
通讯作者：
Bailly-Maitre, Beatrice
中科院分区：
文献类型：
--
作者：
Lebeaupin, Cynthia;Vallee, Deborah;Bailly-Maitre, Beatrice
内质网(ER)应激在非酒精性脂肪性肝病(NAFLD)中被激活，增加了内质网应激依赖的代谢功能障碍、炎症和细胞死亡是从脂肪变性转变为脂肪性肝炎(非酒精性脂肪性肝炎；NASH)的可能性。B细胞淋巴瘤2(BCL2)相关的X蛋白(Bax)抑制物1(BI-1)是内质网应激感受器的负性调节因子，肌醇需要酶1α(IRE1)，在NAFLD中作为肝脏保护剂尚未被探索。我们假设，BI-1的基因消融会使肝脏容易受到NASH的影响，因为IRE1信号不受限制。给野生型和BI-1(-/-)小鼠急性注射衣霉素(TM)(1 mg/kg)或高脂饮食(HFD)慢性诱导ER应激，以确定NAFLD的表型。经TM处理的BI-1(-/-)小鼠的肝脏出现IRE1依赖的节点样受体家族、含3个吡咯环的炎性小体激活、肝细胞死亡、肝纤维化和脂类平衡失调，导致一周内肝功能衰竭。对人NAFLD肝活检组织的分析显示，BI-1下调与IRE1内切核酸酶(RNase)信号上调平行。在出现NASH和2型糖尿病的HFD喂养的BI-1(-/-)小鼠中，肝脏IRE1、X-box结合蛋白1(XBP1)和C/EBP同源蛋白(CHOP)的过度表达与激活的NLRP3炎症体和caspase-1/-11有关。IL-1、IL-6、单核细胞趋化蛋白1(MCP1)、趋化因子(C-X-C基序)配体1(CXCL1)和丙氨酸转氨酶(ALT)/天冬氨酸转氨酶(AST)水平升高分别表示炎症和损伤。在高脂诱导的非酒精性脂肪肝模型中，评价了小分子STF-083010或48C对IRE1RNase活性的药理抑制作用。在BI-1(-/-)小鼠中，任何一种治疗都有效地抵消了IRE1 RNase的活性，改善了糖耐量，并从NASH中拯救出来。在原代小鼠肝细胞中，IRE1核糖核酸酶活性在介导NLRP3炎症体激活和细胞死亡中具有肝细胞特异性作用。结论：用药物或BI-1靶向IRE1依赖的NLRP3炎症体信号通路可能是治疗NASH的一种切实的治疗策略。(2018年《肝病》)。
Endoplasmic reticulum (ER) stress is activated in nonalcoholic fatty liver disease (NAFLD), raising the possibility that ER stress-dependent metabolic dysfunction, inflammation, and cell death underlie the transition from steatosis to steatohepatitis (nonalcoholic steatohepatitis; NASH). B-cell lymphoma 2 (BCL2)-associated X protein (Bax) inhibitor-1 (BI-1), a negative regulator of the ER stress sensor, inositol-requiring enzyme 1 alpha (IRE1), 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 because of unrestrained IRE1 signaling. ER stress was induced in wild-type and BI-1(-/-) mice acutely by tunicamycin (TM) injection (1 mg/kg) or chronically by high-fat diet (HFD) feeding to determine NAFLD phenotype. Livers of TM-treated BI-1(-/-) mice showed IRE1-dependent NOD-like receptor family, pyrin domain containing 3 (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 down-regulation parallel to the up-regulation of IRE1 endoribonuclease (RNase) signaling. In HFD-fed BI-1(-/-) mice that presented NASH and type 2 diabetes, exaggerated hepatic IRE1, X-box binding protein 1 (XBP1), and C/EBP homologous protein (CHOP) expression was linked to activated NLRP3 inflammasome and caspase-1/-11. Rises in interleukin (IL)-1, IL-6, monocyte chemoattractant protein 1 (MCP1), chemokine (C-X-C motif) ligand 1 (CXCL1), and alanine transaminase (ALT)/aspartate transaminase (AST) levels revealed significant inflammation and injury, respectively. Pharmacological inhibition of IRE1 RNase activity with the small molecules, STF-083010 or 48c, was evaluated in HFD-induced NAFLD. In BI-1(-/-) mice, either treatment effectively counteracted IRE1 RNase activity, improving glucose tolerance and rescuing from NASH. The hepatocyte-specific role of IRE1 RNase activity in mediating NLRP3 inflammasome activation and cell death was confirmed in primary mouse hepatocytes by IRE1 axis knockdown or its inhibition with STF-083010 or 48c. Conclusion: Targeting IRE1-dependent NLRP3 inflammasome signaling with pharmacological agents or by BI-1 may represent a tangible therapeutic strategy for NASH. (Hepatology 2018).