Transcriptional regulation of X-Box-binding protein One (XBP1) by hepatocyte nuclear factor 4- (HNF4-) Is vital to beta-cell function

The transcription factor, X-box-binding protein-1 (XBP1), controls the development and maintenance of the endoplasmic reticulum (ER) in multiple secretory cell lineages.Weshow 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 Ca²⁺ signaling; we show that diminished XBP1 and/or HNF4α in β-cells led to impaired ER Ca²⁺ 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.