title: Hepatic nuclear factor 1alpha (HNF1alpha) dysfunction down-regulates X-box-binding protein 1 (XBP1) and sensitizes beta-cells to endoplasmic reticulum stress.
abstract: Correct endoplasmic reticulum (ER) function is critical for the health of secretory cells, such as the pancreatic β-cell, and ER stress is often a contributory factor to β-cell death in type 2 diabetes. We have used an insulin-secreting cell line with inducible expression of dominant negative (DN) HNF1α, a transcription factor vital for correct β-cell development and function, to show that HNF1α is required for Xbp1 transcription and maintenance of the normal ER stress response. DN HNF1α expression sensitizes the β-cell to ER stress by directly down-regulating Xbp1 transcription, whereas Atf6 is unaffected. Furthermore, DN HNF1α alters calcium homeostasis, resulting in elevated cytoplasmic calcium and increased store-operated calcium entry, whereas mitochondrial calcium uptake is normal. Loss of function of XBP1 is toxic to the β-cell and decreases production of the ER chaperone BiP, even in the absence of ER stress. DN HNF1α-induced sensitivity to cyclopiazonic acid can be partially rescued with the chemical chaperone tauroursodeoxycholate. Rat insulin 2 promoter-DN HNF1α mouse islets express lower levels of BiP mRNA, synthesize less insulin, and are sensitized to ER stress relative to matched control mouse islets, suggesting that this mechanism is also operating in vivo.
authors.affiliation: Department of Cell Physiology and Metabolism, Centre Médical Universitaire, Université de Genève, 1 Rue Michel-Servet, 1211 Genève 4, Switzerland.
authors.forename: Clare L
authors.initials: CL
authors.lastname: Kirkpatrick
authors.forename: Andreas
authors.initials: A
authors.lastname: Wiederkehr
authors.forename: Mathurin
authors.initials: M
authors.lastname: Baquié
authors.forename: Dmitry
authors.initials: D
authors.lastname: Akhmedov
authors.forename: Haiyan
authors.initials: H
authors.lastname: Wang
authors.forename: Benoit R
authors.initials: BR
authors.lastname: Gauthier
authors.forename: Ildem
authors.initials: I
authors.lastname: Akerman
authors.forename: Hisamitsu
authors.initials: H
authors.lastname: Ishihara
authors.forename: Jorge
authors.initials: J
authors.lastname: Ferrer
authors.forename: Claes B
authors.initials: CB
authors.lastname: Wollheim
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000096:biosynthesis* / Q000235:genetics; D015536:Down-Regulation / Q000502:physiology*; D004721:Endoplasmic Reticulum / Q000235:genetics / Q000378:metabolism; D000091342:Endoplasmic Reticulum Chaperone BiP; D057809:HEK293 Cells; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism; D051538:Hepatocyte Nuclear Factor 1-alpha / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007328:Insulin / Q000235:genetics / Q000378:metabolism; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D011401:Promoter Regions, Genetic / Q000502:physiology; D051381:Rats; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors / Q000096:biosynthesis* / Q000235:genetics; D014158:Transcription, Genetic / Q000502:physiology; D056811:Unfolded Protein Response / Q000502:physiology*; D000071717:X-Box Binding Protein 1
chemical_list: D004268:DNA-Binding Proteins; D000091342:Endoplasmic Reticulum Chaperone BiP; C051684:GRP78 protein, rat; D006360:Heat-Shock Proteins; D051538:Hepatocyte Nuclear Factor 1-alpha; C496488:Hnf1a protein, mouse; C496489:Hnf1a protein, rat; 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; C000605545:Xbp1 protein, rat; D002118:Calcium