IRE1α-XBP1s induces PDI expression to increase MTP activity for hepatic VLDL assembly and lipid homeostasis

Cell Metab. 2012 Oct 3;16(4):473-86. doi: 10.1016/j.cmet.2012.09.003.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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

Substances

  • Carrier Proteins
  • DNA-Binding Proteins
  • Lipoproteins, VLDL
  • Regulatory Factor X Transcription Factors
  • Transcription Factors
  • Triglycerides
  • X-Box Binding Protein 1
  • Xbp1 protein, mouse
  • microsomal triglyceride transfer protein
  • Ern1 protein, mouse
  • Protein-Serine-Threonine Kinases
  • Endoribonucleases
  • Protein Disulfide-Isomerases