The role of IRE1a in lipid homeostasis

The endoplasmic reticulum (ER) is a vital organelle to coordinate multiple synthetic and secretive pathways in the liver. Perturbation of ER homeostasis induces ER stress and causes lipid accumulation in the liver. To maintain ER homeostasis, a complex protective response termed the unfolded protein response (UPR) has evolved. The UPR has also emerged as an essential signaling pathway to regulate hepatic lipid metabolism. However, the physiological role of inositol-requiring transmembrane kinase and endonuclease 1 (IRE1), the most conserved arm in the UPR, is not well defined in hepatocytes. Therefore, to determine the function of IRE1a; in hepatocytes, we generated a conditional deletion of Ire1a; in hepatocytes by transgenic expression of Cre under the control of the albumin promoter. We found that the Ire1a; hepatocyte-specific null animals were hypocholesterolemic and hypotriglyceridemic accompanied by marginally increased accumulation of triglyceride (TG) in the liver. We also found that Ire1a; hepatocyte-specific null animals had impaired VLDL-TG secretion with unaltered lipogenesis. Further analysis on lipid contents of cytosol and smooth ER indicates that hepatocyte-specific deletion of Ire1a; reduces lipid partitioning into the ER lumen to decrease the assembly of triglyceride (TG)-rich VLDL. Through metabolic labeling studies using primary hepatocytes, we further revealed a reduced sER-TG accretion as a key underlying cellular mechanism for defective TG-rich VLDL assembly in Ire1a;-deleted hepatocytes. Finally, proteomic analysis and genetic complementation approaches demonstrated that this defect in TG-rich VLDL assembly is caused in large part by reduced MTP activity due to decreased expression of PDI. Collectively, our findings reveal a key role for the IRE1a;-XBP1s-PDI axis in linking ER homeostasis with regulation of VLDL production and hepatic lipid homeostasis.