| First Author | Wang JM | Year | 2018 |
| Journal | Sci Signal | Volume | 11 |
| Issue | 530 | PubMed ID | 29764990 |
| Mgi Jnum | J:284455 | Mgi Id | MGI:6381253 |
| Doi | 10.1126/scisignal.aao4617 | Citation | Wang JM, et al. (2018) IRE1alpha prevents hepatic steatosis by processing and promoting the degradation of select microRNAs. Sci Signal 11(530) |
| abstractText | Obesity or a high-fat diet represses the endoribonuclease activity of inositol-requiring enzyme 1alpha (IRE1alpha), 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 IRE1alpha 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 IRE1alpha processed a subset of precursor miRNAs in the liver, including those of the miR-200 and miR-34 families, such that IRE1alpha 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 IRE1alpha 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 alpha (PPARalpha) and the deacetylase sirtuin 1 (SIRT1), regulators of fatty acid oxidation and triglyceride lipolysis. IRE1alpha 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 IRE1alpha maintains lipid homeostasis through its regulation of miRNAs, a regulatory pathway distinct from the canonical IRE1alpha-UPR pathway under acute ER stress. |
