title: Transcriptional Regulation of X-Box-binding Protein One (XBP1) by Hepatocyte Nuclear Factor 4α (HNF4Α) Is Vital to Beta-cell Function.
abstract: 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.
authors.affiliation: From the Division of Gastroenterology, Departments of Medicine, Pathology & Immunology, and Developmental Biology, Washington University, St. Louis, Missouri 63110.
authors.forename: Benjamin D
authors.initials: BD
authors.lastname: Moore
authors.affiliation: From the Division of Gastroenterology, Departments of Medicine, Pathology & Immunology, and Developmental Biology, Washington University, St. Louis, Missouri 63110.
authors.forename: Ramon U
authors.initials: RU
authors.lastname: Jin
authors.affiliation: From the Division of Gastroenterology, Departments of Medicine, Pathology & Immunology, and Developmental Biology, Washington University, St. Louis, Missouri 63110.
authors.forename: Heiyong
authors.initials: H
authors.lastname: Lo
authors.affiliation: From the Division of Gastroenterology, Departments of Medicine, Pathology & Immunology, and Developmental Biology, Washington University, St. Louis, Missouri 63110.
authors.forename: Min
authors.initials: M
authors.lastname: Jung
authors.affiliation: Roche Pharma Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd, Grenzacherstrasse 124, CH-4070 Basel, Switzerland.
authors.forename: Haiyan
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Cell Biology, Neurobiology, and Anatomy, Medical College of Wisconsin, Milwaukee, Wisconsin 53226.
authors.forename: Michele A
authors.initials: MA
authors.lastname: Battle
authors.affiliation: Lund University Diabetes Center, Department of Clinical Sciences, Diabetes & Endocrinology, Skåne University Hospital, Lund University, Malmö 20502, Sweden, Department of Cell Physiology and Metabolism, Université de Genève, University Medical Centre, 1 rue Michel-Servet, Geneva 4 1211, Switzerland, and.
authors.forename: Claes B
authors.initials: CB
authors.lastname: Wollheim
authors.affiliation: Division of Endocrinology, Departments of Medicine, Metabolism, and Lipid Research, Washington University School of Medicine, St. Louis, Missouri 63110.
authors.forename: Fumihiko
authors.initials: F
authors.lastname: Urano
authors.affiliation: From the Division of Gastroenterology, Departments of Medicine, Pathology & Immunology, and Developmental Biology, Washington University, St. Louis, Missouri 63110, jmills@wustl.edu.
authors.forename: Jason C
authors.initials: JC
authors.lastname: Mills
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics; D004721:Endoplasmic Reticulum / Q000378:metabolism; D005786:Gene Expression Regulation; D005947:Glucose / Q000502:physiology; D057809:HEK293 Cells; D051557:Hepatocyte Nuclear Factor 4 / Q000502:physiology*; D006706:Homeostasis; D006801:Humans; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000502:physiology*; D051379:Mice; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D014158:Transcription, Genetic; D000071717:X-Box Binding Protein 1
chemical_list: D004268:DNA-Binding Proteins; D051557:Hepatocyte Nuclear Factor 4; C496593:Hnf4a protein, mouse; D007328:Insulin; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors; D000071717:X-Box Binding Protein 1; C000605543:XBP1 protein, human; C000605544:Xbp1 protein, mouse; D005947:Glucose; D002118:Calcium
keywords: X-box binding protein 1 (XBP1); beta cell (B-cell); endoplasmic reticulum (ER); hepatocyte nuclear factor 4 (HNF-4); insulin secretion