The unfolded protein response transducer IRE1α prevents ER stress-induced hepatic steatosis

Abstract

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 α (IRE1α), 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 IRE1α‐mediated signalling in the liver, we generated hepatocyte‐specific Ire1α‐null mice by utilizing an albumin promoter‐controlled Cre recombinase‐mediated deletion. Deletion of Ire1α 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 IRE1α is required to maintain the secretion efficiency of selective proteins. In the absence of ER stress, mice with hepatocyte‐specific Ire1α deletion displayed modest hepatosteatosis that became profound after induction of ER stress. Further investigation revealed that IRE1α represses expression of key metabolic transcriptional regulators, including CCAAT/enhancer‐binding protein (C/EBP) β, C/EBPδ, peroxisome proliferator‐activated receptor γ (PPARγ), and enzymes involved in triglyceride biosynthesis. IRE1α was also found to be required for efficient secretion of apolipoproteins upon disruption of ER homeostasis. Consistent with a role for IRE1α in preventing intracellular lipid accumulation, mice with hepatocyte‐specific deletion of Ire1α 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 IRE1α as a key regulator to prevent hepatic steatosis provides novel insights into ER stress mechanisms in fatty liver diseases associated with toxic liver injuries.

Hepatic IRE1α regulates fasting-induced metabolic adaptive programs through the XBP1s–PPARα axis signalling

“…Our results demonstrate that the IRE1a-XBP1 branch of the UPR serves as an unanticipated mechanism that underlies the transcriptional induction of Ppara in response to food deprivation 30,31 . Notably, Wang et al 18,19 did not document changes in the expression of Ppara in their liver-specific Ire1a knockout mice, most likely due to the short period of fasting in the reported studies. In addition, liver microarray analyses by So et al 17 in their liver-specific Xbp1 knockout mice also did not reveal expression changes in Ppara target genes, which may be ascribable to the non-fasting conditions or owing to XBP1-deficiency-induced hyperactivation of IRE1a for its mRNA decay actions in this model.…”

“…Studies in animal models have implicated IRE1a or XBP1s in both glucose and lipid metabolism 6,8,9,[13][14][15][16][17][18][19][20] . Recently, it was shown that the hepatic IRE1a-XBP1 pathway is activated upon refeeding, and overexpression of XBP1s in livers of mice may promote postprandial metabolic changes 6 .…”

Excess iron modulates endoplasmic reticulum stress-associated pathways in a mouse model of alcohol and high-fat diet-induced liver injury

“…34 Given the role of IRE1a in preventing ER stress-induced hepatic steatosis, the suppression of JNK may reflect its role in nonapoptotic stress signaling responses in the development of hepatic injury secondary to iron, ethanol, and obesity. 35 To strengthen the argument for the role of iron in ER stress, we also examined pathways that are related to the UPR. A dysfunctional UPR may be a precursor for impaired autophagy, Iron toxicity in alcoholic liver disease TCH Tan et al disrupted containment of toxic cytosolic waste products, and subsequent activation of stress and proinflammatory signaling pathways.…”

PKA phosphorylation couples hepatic inositol-requiring enzyme 1α to glucagon signaling in glucose metabolism

“…These data suggest that phosphorylation of hepatic IRE1α at Ser 724 , which is also targeted by PKA, dictates the functional output of IRE1α, and may constitute a key step in glucagon regulation of the gluconeogenic program. As genetic ablation of hepatic IRE1α or XBP1 has been shown to affect lipid metabolism (24,29,30), we wondered whether XBP1 can mediate IRE1α's effect on the up-regulation of gluconeogenic genes. Surprisingly, adenoviral overexpression in hepatocytes of the spliced form of XBP1 (SI Appendix, Fig.…”