TY - JOUR
T1 - IRE1α-XBP1s induces PDI expression to increase MTP activity for hepatic VLDL assembly and lipid homeostasis
AU - Wang, Shiyu
AU - Chen, Zhouji
AU - Lam, Vivian
AU - Han, Jaeseok
AU - Hassler, Justin
AU - Finck, Brian N.
AU - Davidson, Nicholas O.
AU - Kaufman, Randal J.
N1 - Funding Information:
This work was supported by NIH grants P01HL057346, R37DK042394, R01DK088227, R24DK093074, and R01HL052173 to R.J.K.; grants HL-38180, DK-56260, and DK-52574 to N.O.D.; DK-78187 to B.N.F.; and an AHA postdoctoral fellowship to S.W. We thank Dr. Benny Hung-Junn Chang, for ADRP antibody; Dr. Yong Liu for wild-type IRE1α, kinase-dead IRE1α, and RNase-dead IRE1α adenovirus; Dr. Umut Ozcan for XBP1(s) adenovirus; Dr. Stuart Lipton for PDI and PDImu adenovirus; Dr. John Bergeron for generating EM micrographs; and Dr. Henry Ginsberg and Dr. Richard Lehner for insightful advice. S.W. and Z.C. conceived and designed the experiments with R.J.K.; S.W., Z.C., V.L., and J.H. performed the experiments; S.W. and Z.C. wrote the paper with R.J.K.; B.N.F. and N.O.D. provided technical support.
PY - 2012/10/3
Y1 - 2012/10/3
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84867063735&partnerID=8YFLogxK
U2 - 10.1016/j.cmet.2012.09.003
DO - 10.1016/j.cmet.2012.09.003
M3 - Article
C2 - 23040069
AN - SCOPUS:84867063735
SN - 1550-4131
VL - 16
SP - 473
EP - 486
JO - Cell metabolism
JF - Cell metabolism
IS - 4
ER -