The Xbp1s/GalE axis links ER stress to postprandial hepatic metabolism

J Clin Invest. 2013 Jan;123(1):455-68. doi: 10.1172/JCI62819. Epub 2012 Dec 21.

Abstract

Postprandially, the liver experiences an extensive metabolic reprogramming that is required for the switch from glucose production to glucose assimilation. Upon refeeding, the unfolded protein response (UPR) is rapidly, though only transiently, activated. Activation of the UPR results in a cessation of protein translation, increased chaperone expression, and increased ER-mediated protein degradation, but it is not clear how the UPR is involved in the postprandial switch to alternate fuel sources. Activation of the inositol-requiring enzyme 1 (IRE1) branch of the UPR signaling pathway triggers expression of the transcription factor Xbp1s. Using a mouse model with liver-specific inducible Xbp1s expression, we demonstrate that Xbp1s is sufficient to provoke a metabolic switch characteristic of the postprandial state, even in the absence of caloric influx. Mechanistically, we identified UDP-galactose-4-epimerase (GalE) as a direct transcriptional target of Xbp1s and as the key mediator of this effect. Our results provide evidence that the Xbp1s/GalE pathway functions as a novel regulatory nexus connecting the UPR to the characteristic postprandial metabolic changes in hepatocytes.

Publication types

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

MeSH terms

  • Animals
  • Cells, Cultured
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • Endoplasmic Reticulum-Associated Degradation / physiology*
  • Hepatocytes / cytology
  • Hepatocytes / metabolism*
  • Liver / cytology
  • Liver / metabolism*
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism
  • Mice
  • Mice, Transgenic
  • Postprandial Period / physiology*
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism
  • Rabbits
  • Regulatory Factor X Transcription Factors
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • UDPglucose 4-Epimerase / genetics
  • UDPglucose 4-Epimerase / metabolism*
  • X-Box Binding Protein 1

Substances

  • DNA-Binding Proteins
  • Membrane Proteins
  • Regulatory Factor X Transcription Factors
  • Transcription Factors
  • X-Box Binding Protein 1
  • Xbp1 protein, mouse
  • Ern2 protein, mouse
  • Protein-Serine-Threonine Kinases
  • UDPglucose 4-Epimerase