IRE1α-XBP1s Induces PDI Expression to Increase MTP Activity for Hepatic VLDL Assembly and Lipid Homeostasis

Abstract

Summary The unfolded protein response (UPR) is a signaling pathway required to maintain endoplasmic reticulum (ER) homeostasis and hepatic lipid metabolism. Here, we identify an essential role for the inositol-requiring transmembrane kinase/endoribonuclease 1α (IRE1α)-X-box binding protein 1 (XBP1) arm of the UPR in regulation of hepatic very low-density lipoprotein (VLDL) assembly and secretion. Hepatocyte-specific deletion of Ire1α reduces lipid partitioning into the ER lumen and impairs the assembly of triglyceride (TG)-rich VLDL, but does not affect TG synthesis, de novo lipogenesis, or the synthesis or secretion of apolipoprotein B (apoB). The defect in VLDL assembly is, at least in part, due to decreased microsomal triglyceride-transfer protein (MTP) activity resulting from reduced protein disulfide isomerase (PDI) expression. Collectively, our findings reveal a key role for the IRE1α-XBP1s-PDI axis in linking ER homeostasis with regulation of VLDL production and hepatic lipid homeostasis that may provide a therapeutic target for disorders of lipid metabolism.

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

“…3e) and showed impaired hepatic VLDL secretion ( Supplementary Fig. 3f), supporting the role of the IRE1a pathway in hepatic VLDL assembly and secretion that was recently reported 18 . Furthermore, we observed a pronounced reduction in the level of circulating fibroblast growth factor 21 (FGF21) in fasted LKO animals (Fig.…”

“…2i), critical enzymes in b-oxidation and ketogenesis. Together, these data suggest a crucial role for hepatic IRE1a in promoting prolonged fasting-induced fatty acid b-oxidation and ketogenesis through influencing PPARa-dependent gene expression programs, in addition to regulating VLDL assembly and secretion 18 .…”

“…XBP1s, the potent transcription factor resulting from activation of the RNase activity of IRE1a, controls a key gene expression programme that copes with ER stress. Emerging evidence indicates that XBP1s also exerts its metabolic effects through regulating effector genes such as protein disulphide isomerase 18 or UDP-galactose-4-epimerase 6 , or through non-transcriptional actions such as promoting degradation of the Forkhead box O1 transcription factor 20 . Nonetheless, it remains largely nebulous how IRE1a integrates metabolic signals under physiological settings to execute its functions through generating the endogenous XBP1s protein.…”

“…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 .…”

“…Hepatic overexpression of XBP1s was also reported to exert a suppressive effect upon gluconeogenesis 15,20 . In addition, the hepatic IRE1a-XBP1 pathway was shown to play a crucial role in the assembly of very low-density lipoprotein (VLDL) and hepatic lipid homoeostasis through regulation of protein disulphide isomerase expression 18 . Despite these recent progresses, it remains largely elusive how IRE1a acts under physiological conditions through the Xbp1 mRNA-splicing event to regulate metabolic pathways.…”