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. We show here that Hepatocyte Nuclear Factor 4 (HNF4) directly induces XBP1 expression. Mutations in HNF4 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 HNF4 caused decreased expression of XBP1 and reduced cellular ER networks. GSIS depends on ER Ca2+ signaling; we show that diminished XBP1 and/or HNF4 in -cells led to impaired ER Ca2+ homeostasis. Restoring XBP1 expression was sufficient to completely rescue GSIS in HNF4- deficient -cells. Our findings uncover a transcriptional relationship between HNF4 and Xbp1 with potentially broader implications about MODYI and the importance of transcription factor signaling in the regulation of secretion.