IRE1α 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 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.

NADPH and glutathione redox link TCA cycle activity to endoplasmic reticulum stress

“…Whatever the case, we infer that inhibiting TCA activity actually protects ER 24 homeostasis in part because of its effects on ER ultrastructure. In principle, a hyperoxidizing ER 25 might simply blunt the UPR rather than improve ER function, since activation of at least the UPR 26 sensors ATF6 and IRE1 can be inhibited by oxidation (Nadanaka, Okada, Yoshida, & Mori, 1 2007; J. M. Wang et al, 2018). However, there is no evidence that enforcing reduction of these 2 sensors is sufficient for their activation, meaning there would then be no reason to expect DCA 3 to cause ER stress on its own.…”

Unfolded Protein Response Sensors in Hepatic Lipid Metabolism and Nonalcoholic Fatty Liver Disease

“…121 New RIDD targets are continually being identified, many of which function in lipid metabolism such as DGAT2, ACC2, and PCSK9. 35,69,122 It has recently become recognized that IRE1α is subject to iNos-mediated S-nitrosylation thereby inhibiting both XBP1 splicing and RIDD. 122,123 Inhibition of RIDD via this mechanism has been shown to increase the abundance of microRNAs involved in lipid mobilization and thereby exacerbate hepatic steatosis.…”

Hepatocyte-specific deletion of XBP1 sensitizes mice to liver injury through hyperactivation of IRE1α

“…Indeed, IRE1α activity has been implicated as a contributing factor to lipotoxic liver injury and nonalcoholic fatty liver disease [36,37]. Still, not all research points to heightened IRE1α activity as a driving factor in liver disease pathogenesis; in some instances, S-nitrosylation of IRE1α, which impairs its endoribonuclease activity, has been linked to the development of hepatic steatosis [34,38]. Given the disconnection between hepatic steatosis and liver injury in our experiments, we conclude that IRE1α activation is detrimental to the liver independent of its effect on hepatic steatosis.…”