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 nonalcoholic fatty liver disease (NAFLD), which is caused by lipid accumulation in the liver. 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.

中文翻译：

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IRE1α通过加工和促进特定microRNA的降解来预防肝脂肪变性。

肥胖或高脂饮食会抑制需要肌醇的酶1α（IRE1α）的核糖核酸内切酶活性，这是内质网（ER）胁迫下细胞中未折叠蛋白反应（UPR）的传递子。UPR受损与肝脏脂肪变性和非酒精性脂肪肝疾病（NAFLD）有关，这是由肝脏中脂质的积累引起的。我们发现，IRE1α通过抑制调节脂质动员的microRNA（miRNA）的生物合成，对于维持肝脏脂质稳态起着至关重要的作用。在正常食物喂养的小鼠中，IRE1α的核糖核酸内切酶功能在肝脏中处理了一部分前体miRNA，包括miR-200和miR-34家族的那些，因此IRE1α通过受IRE1依赖性调节的衰变过程促进了它们的降解（ RIDD）。小鼠高脂饮食或肝脂肪变性与IRE1α的S-亚硝基化及其内切核糖核酸酶活性失活有关。这导致这些miRNA家族在肝脏中的丰度增加，因此其靶标的丰度降低，其中包括过氧化物酶体增殖物激活的受体α（PPARα）和脱乙酰酶沉默调节蛋白1（SIRT1），脂肪酸氧化调节剂和甘油三酸酯脂解。IRE1α缺乏症加重了小鼠的肝脂肪变性。在培养的脂质超载的肝细胞和肝脂肪变性患者的肝脏中，miR-200和miR-34家族的丰度也增加了。我们的发现揭示了IRE1α通过调控miRNA维持脂质稳态的机制，