Transcriptional Regulation of X-Box-binding Protein One (XBP1) by Hepatocyte Nuclear Factor 4α (HNF4Α) Is Vital to Beta-cell Function

J Biol Chem. 2016 Mar 18;291(12):6146-57. doi: 10.1074/jbc.M115.685750. Epub 2016 Jan 20.


The transcription factor, X-box-binding protein-1 (XBP1), controls the development and maintenance of the endoplasmic reticulum (ER) in multiple secretory cell lineages. We show here that Hepatocyte Nuclear Factor 4α (HNF4α) directly induces XBP1 expression. Mutations in HNF4α cause Mature-Onset Diabetes of the Young I (MODYI), a subset of diabetes characterized by diminished GSIS. In mouse models, cell lines, and ex vivo islets, using dominant negative and human- disease-allele point mutants or knock-out and knockdown models, we show that disruption of HNF4α caused decreased expression of XBP1 and reduced cellular ER networks. GSIS depends on ER Ca(2+) signaling; we show that diminished XBP1 and/or HNF4α in β-cells led to impaired ER Ca(2+) homeostasis. Restoring XBP1 expression was sufficient to completely rescue GSIS in HNF4α-deficient β-cells. Our findings uncover a transcriptional relationship between HNF4α and Xbp1 with potentially broader implications about MODYI and the importance of transcription factor signaling in the regulation of secretion.

Keywords: X-box binding protein 1 (XBP1); beta cell (B-cell); endoplasmic reticulum (ER); hepatocyte nuclear factor 4 (HNF-4); insulin secretion.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Calcium / metabolism
  • Cell Line
  • DNA-Binding Proteins / genetics*
  • DNA-Binding Proteins / metabolism
  • Diabetes Mellitus, Type 2 / genetics
  • Endoplasmic Reticulum / metabolism
  • Gene Expression Regulation
  • Glucose / physiology
  • HEK293 Cells
  • Hepatocyte Nuclear Factor 4 / physiology*
  • Homeostasis
  • Humans
  • Insulin / metabolism
  • Insulin Secretion
  • Insulin-Secreting Cells / physiology*
  • Mice
  • Regulatory Factor X Transcription Factors
  • Transcription Factors / genetics*
  • Transcription Factors / metabolism
  • Transcription, Genetic*
  • X-Box Binding Protein 1


  • DNA-Binding Proteins
  • Hepatocyte Nuclear Factor 4
  • Hnf4a protein, mouse
  • Insulin
  • Regulatory Factor X Transcription Factors
  • Transcription Factors
  • X-Box Binding Protein 1
  • XBP1 protein, human
  • Xbp1 protein, mouse
  • Glucose
  • Calcium