IRE1α prevents hepatic steatosis by processing and promoting the degradation of select microRNAs.
IRE1α prevents hepatic steatosis by processing and promoting the degradation of select microRNAs.
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DOI：
10.1126/scisignal.aao4617
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发表时间：
2018-05-15
影响因子：
7.3
通讯作者：
Zhang K
中科院分区：
文献类型：
--
作者：
Wang JM;Qiu Y;Yang Z;Kim H;Qian Q;Sun Q;Zhang C;Yin L;Fang D;Back SH;Kaufman RJ;Yang L;Zhang K
肥胖或高脂饮食抑制肌醇需要酶1α（IRE 1 α）的核糖核酸内切酶活性，IRE 1 α是内质网（ER）应激下细胞中未折叠蛋白反应（UPR）的转导子。UPR受损与肝脏脂肪变性和非酒精性脂肪性肝病（NAFLD）相关，后者由肝脏中的脂质积聚引起。在这里，我们发现IRE 1 α通过抑制调节脂质动员的microRNA（miRNAs）的生物合成，对维持肝脏中的脂质稳态至关重要。在喂食正常食物的小鼠中，IRE 1 α的核糖核酸内切酶功能处理肝脏中的前体miRNA子集，包括miR-200和miR-34家族的那些，使得IRE 1 α通过调节IRE 1依赖性衰变（RIDD）过程促进它们的降解。小鼠的高脂饮食或患者的肝脂肪变性与IRE 1 α的S-亚硝基化及其内切核糖核酸酶活性的失活有关。这导致肝脏中这些miRNA家族的丰度增加，因此，其靶点的丰度减少，包括过氧化物酶体增殖物激活受体α（PPARα）和去乙酰化酶sirtuin 1（SIRT 1），脂肪酸氧化和甘油三酯脂解的调节剂。IRE 1 α缺乏可加重小鼠肝脂肪变性。miR-200和miR-34家族的丰度在培养的脂质超载肝细胞和肝脂肪变性患者的肝脏中也增加。我们的研究结果揭示了IRE 1 α通过调节miRNAs维持脂质稳态的机制，这一调节途径与急性ER应激下的经典IRE 1 α-UPR途径不同。
Obesity or a high-fat diet represses the endoribonuclease activity of inositol-requiring enzyme 1α (IRE1α), a transducer of the unfolded protein response (UPR) in cells under endoplasmic reticulum (ER) stress. An impaired UPR is associated with hepatic steatosis and non-alcoholic fatty liver disease (NAFLD), which is caused by lipid accumulation in the liver. Here, we found that IRE1α was critical to maintaining lipid homeostasis in the liver by repressing the biogenesis of microRNAs (miRNAs) that regulate lipid mobilization. In mice fed normal chow, the endoribonuclease function of IRE1α processed a subset of precursor miRNAs in the liver, including those of the miR-200 and miR-34 families, such that IRE1α promoted their degradation through the process of regulated IRE1-dependent decay (RIDD). A high-fat diet in mice or hepatic steatosis in patients was associated with the S-nitrosylation of IRE1α and inactivation of its endoribonuclease activity. This resulted in an increased abundance of these miRNA families in the liver and, consequently, a decreased abundance of their targets, which included peroxisome proliferator-activated receptor α (PPARα) and the deacetylase sirtuin 1 (SIRT1), regulators of fatty acid oxidation and triglyceride lipolysis. IRE1α deficiency exacerbated hepatic steatosis in mice. The abundance of the miR-200 and miR-34 families was also increased in cultured, lipid-overloaded hepatocytes and in the livers of patients with hepatic steatosis. Our findings reveal a mechanism by which IRE1α maintains lipid homeostasis through its regulation of miRNAs, a regulatory pathway distinct from the canonical IRE1α-UPR pathway under acute ER stress.
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成纤维细胞生长因子 21 受未折叠蛋白反应的 IRE1 α-XBP1 分支调节并抵消内质网应激诱导的肝脂肪变性
影响因子：
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作者：
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影响因子：
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发表时间：
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影响因子：
4.1
作者：
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