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

• Published in: Cell metabolism 2012-10, Vol.16 (4), p.473-486
• Main Authors: Wang, Shiyu, Chen, Zhouji, Lam, Vivian, Han, Jaeseok, Hassler, Justin, Finck, Brian N., Davidson, Nicholas O., Kaufman, Randal J.
• Format: Article
• Language: English
• Subjects: Animals; Carrier Proteins - metabolism; DNA-Binding Proteins - metabolism; Endoribonucleases - antagonists & inhibitors; Endoribonucleases - genetics; Endoribonucleases - metabolism; Hepatocytes - metabolism; Lipid Metabolism - physiology; Lipoproteins, VLDL - metabolism; Mice; Mice, Knockout; Protein Disulfide-Isomerases - metabolism; Protein-Serine-Threonine Kinases - antagonists & inhibitors; Protein-Serine-Threonine Kinases - genetics; Protein-Serine-Threonine Kinases - metabolism; Regulatory Factor X Transcription Factors; Transcription Factors - metabolism; Triglycerides - metabolism; Unfolded Protein Response; X-Box Binding Protein 1
• ISSN: 1550-4131; 1932-7420
• DOI: 10.1016/j.cmet.2012.09.003

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. [Display omitted] ► Ire1α deletion impairs hepatic VLDL assembly, but not lipogenesis or apoB secretion ► IRE1α-XBP1s regulates TG partitioning into the smooth ER for VLDL assembly ► Inactivation of IRE1α in hepatocytes reduces PDI expression and MTP activity ► PDI restores MTP function and promotes VLDL secretion in Ire1α-deleted hepatocytes