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Original article
Gene expression dynamics after murine pancreatitis unveils novel roles for Hnf1α in acinar cell homeostasis
  1. Xavier Molero1,
  2. Eva Cristina Vaquero1,2,
  3. Marta Flández3,
  4. Ana María González1,
  5. Maria Ángels Ortiz1,
  6. Elena Cibrián-Uhalte3,
  7. Joan-Marc Servitja4,5,
  8. Anna Merlos6,7,
  9. Núria Juanpere8,
  10. Mohammad Massumi7,
  11. Anouchka Skoudy7,
  12. Raymond MacDonald9,
  13. Jorge Ferrer5,10,
  14. Francisco X Real3,6
  1. 1Grup de Recerca en Patologia Pancreàtica Exocrina, Hospital Universitari Vall d'Hebron, Institut de Recerca (VHIR), Universitat Autònoma de Barcelona, CIBER-EHD, Barcelona, Spain
  2. 2Department of Gastroenterology, Institut de Malalties Digestives i Metabòliques, Hospital Clínic, CIBEREHD, IDIBAPS, Barcelona, Spain
  3. 3Programa de Patología Molecular, Centro Nacional de Investigaciones Oncológicas, Madrid, Spain
  4. 4Laboratory of Diabetes and Obesity, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Hospital Clinic, Barcelona, Spain
  5. 5Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas, Barcelona, Spain
  6. 6Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra, Barcelona, Spain
  7. 7Programa de Recerca en Càncer, Institut Municipal d'Investigació Mèdica-Hospital del Mar, Barcelona, Spain
  8. 8Department of Pathology, Hospital del Mar-Parc de Salut Mar, Barcelona, Spain
  9. 9Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, Texas, USA
  10. 10Genomic Programming of Beta-Cells Laboratory, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Hospital Clinic, Barcelona, Spain
  1. Correspondence to Dr Xavier Molero, Grup de Recerca en Patologia Pancreàtica Exocrina, Institut de Recerca Hospital Universitari Vall d'Hebron, Pg Vall d'Hebron 119-129, Barcelona 08035, Spain; xmolero{at}ir.vhebron.net Paco Real, Epithelial Carcinogenesis, Group Molecular Pathology, Programme Centro Nacional de Investigaciones Oncológicas, Melchor Fernández Almagro, Madrid, Spain; freal{at}cnio.es

Abstract

Objectives During pancreatitis, specific transcriptional programmes govern functional regeneration after injury. The objective of this study was to analyse the dynamic regulation of pancreatic genes and the role of transcriptional regulators during recovery from pancreatitis.

Design Wild-type and genetically modified mice (Hnf1α−/− and Ptf1a+/−) were used. After caerulein or l-arginine induced pancreatitis, blood or pancreata were processed for enzymatic assays, ELISA, histology, immunohistochemistry, western blotting and quantitative reverse transcriptase-PCR. Nr5a2 promoter reporter and chromatin immunoprecipitation assays for Hnf1α were also performed.

Results After caerulein pancreatic injury, expression of acinar and endocrine genes rapidly decreased, but eventually recovered, depicting distinct cell-type-specific patterns. Pdx1 and Hnf1α mRNAs underwent marked downregulation, matching endocrine/exocrine gene expression profiles. Ptf1a, Pdx1 and Hnf1α protein levels were also reduced and recovered gradually. These changes were associated with transient impairment of exocrine and endocrine function, including abnormal glucose tolerance. On l-arginine pancreatitis, changes in Ptf1a, Pdx1 and Hnf1α gene and protein expression were recapitulated. Reduced Hnf1α and Ptf1a levels after pancreatitis coincided with increased acinar cell proliferation, both in Hnf1α−/− and Ptf1a+/− mice. Moreover, Hnf1α−/− mice had reduced Ptf1a protein as well as transcripts for Ptf1a and digestive enzymes. Dispersed acini from Hnf1α−/− mice showed suboptimal secretory responses to caerulein. Bioinformatics analysis did not support a role for Hnf1α as a direct regulator of digestive enzyme genes. Instead, it was found that Hnf1α binds to, and regulates, the promoter of Nr5a2, coding an orphan nuclear receptor that regulates acinar gene expression.

Conclusions Dynamic changes in gene expression occur on pancreatitis induction, determining altered exocrine and endocrine function. This analysis uncovers roles for Hnf1α in the regulation of acinar cell determination and function. This effect may be mediated, in part, through direct regulation of Nr5a2.

  • Pancreatitis
  • Ptf1a
  • Hnf1α
  • Nr5a2
  • pancreatic fibrosis
  • pancreatic pathology
  • pancreatic cancer
  • cystic fibrosis
  • pancreas
  • pancreatic cancer
  • pancreatitis
  • cancer
  • carcinogenesis
  • pancreatic fibrosis
  • pancreatic physiology
  • diabetes mellitus
  • ageing
  • αß t cells
  • gene expression
  • molecular carcinogenesis
  • mucins
  • epithelial differentiation
  • molecular oncology
  • pancreatic tumours

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Footnotes

  • Funding This work was supported, in part, by: grants PI080342 from Fondo de Investigación Sanitaria and Acción Especial de Genómica (GEN2001-4748-c05-03) to XM; grant PI080280 from Fondo de Investigación Sanitaria to ECV; grants SAF2004-01137, SAF2007-60860, Acción Especial de Genómica (GEN2001-4748-c05-01), and ONCOBIO Consolider from Ministerio de Ciencia e Innovación (Madrid, Spain) to FXR; grant PI080511 from Fondo de Investigación Sanitaria and Acción Especial de Genómica (GEN2001-4748-C05-04) to AS; US Public Health Service grant DK061220 to RJM; and Acción Especial de Genómica (GEN2001-4748-c05-02) to JF. AM was supported by a Juan de la Cierva contract from Ministerio de Ciencia y Tecnología.

  • Competing interests None.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data sharing statement We will provide any data that is cited in the text upon request to X.M. or F. X. R.

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