کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
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2792782 | 1155085 | 2012 | 14 صفحه PDF | دانلود رایگان |

SummaryThe 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.
Graphical AbstractFigure optionsDownload high-quality image (214 K)Download as PowerPoint slideHighlights
► 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
Journal: - Volume 16, Issue 4, 3 October 2012, Pages 473–486