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IRE1? prevents hepatic steatosis by processing and promoting the degradation of select microRNAs.

ABSTRACT: Obesity or a high-fat diet represses the endoribonuclease activity of inositol-requiring enzyme 1? (IRE1?), 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 IRE1? 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 IRE1? processed a subset of precursor miRNAs in the liver, including those of the miR-200 and miR-34 families, such that IRE1? 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 IRE1? 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 ? (PPAR?) and the deacetylase sirtuin 1 (SIRT1), regulators of fatty acid oxidation and triglyceride lipolysis. IRE1? 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 IRE1? maintains lipid homeostasis through its regulation of miRNAs, a regulatory pathway distinct from the canonical IRE1?-UPR pathway under acute ER stress.

SUBMITTER: Wang JM

PROVIDER: S-EPMC6075656 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature

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IRE1α prevents hepatic steatosis by processing and promoting the degradation of select microRNAs.

Wang Jie-Mei JM Qiu Yining Y Yang Zhao Z Kim Hyunbae H Qian Qingwen Q Sun Qinghua Q Zhang Chunbin C Yin Lei L Fang Deyu D Back Sung Hong SH Kaufman Randal J RJ Yang Ling L Zhang Kezhong K

Science signaling 20180515 530

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 regu ...[more]

PMID: 29764990

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Project description:The endoplasmic reticulum (ER) is the cellular organelle responsible for protein folding and assembly, lipid and sterol biosynthesis, and calcium storage. The unfolded protein response (UPR) is an adaptive intracellular stress response to accumulation of unfolded or misfolded proteins in the ER. In this study, we show that the most conserved UPR sensor inositol-requiring enzyme 1 ? (IRE1?), an ER transmembrane protein kinase/endoribonuclease, is required to maintain hepatic lipid homeostasis under ER stress conditions through repressing hepatic lipid accumulation and maintaining lipoprotein secretion. To elucidate physiological roles of IRE1?-mediated signalling in the liver, we generated hepatocyte-specific Ire1?-null mice by utilizing an albumin promoter-controlled Cre recombinase-mediated deletion. Deletion of Ire1? caused defective induction of genes encoding functions in ER-to-Golgi protein transport, oxidative protein folding, and ER-associated degradation (ERAD) of misfolded proteins, and led to selective induction of pro-apoptotic UPR trans-activators. We show that IRE1? is required to maintain the secretion efficiency of selective proteins. In the absence of ER stress, mice with hepatocyte-specific Ire1? deletion displayed modest hepatosteatosis that became profound after induction of ER stress. Further investigation revealed that IRE1? represses expression of key metabolic transcriptional regulators, including CCAAT/enhancer-binding protein (C/EBP) ?, C/EBP?, peroxisome proliferator-activated receptor ? (PPAR?), and enzymes involved in triglyceride biosynthesis. IRE1? was also found to be required for efficient secretion of apolipoproteins upon disruption of ER homeostasis. Consistent with a role for IRE1? in preventing intracellular lipid accumulation, mice with hepatocyte-specific deletion of Ire1? developed severe hepatic steatosis after treatment with an ER stress-inducing anti-cancer drug Bortezomib, upon expression of a misfolding-prone human blood clotting factor VIII, or after partial hepatectomy. The identification of IRE1? as a key regulator to prevent hepatic steatosis provides novel insights into ER stress mechanisms in fatty liver diseases associated with toxic liver injuries.

Dataset Information

IRE1? prevents hepatic steatosis by processing and promoting the degradation of select microRNAs.

Publications

IRE1α prevents hepatic steatosis by processing and promoting the degradation of select microRNAs.

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