Gene expression dynamics after murine pancreatitis unveils novel roles for Hnf1α in acinar cell homeostasis

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 (Hnf1 alpha(-/-) 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 Hnf1 alpha 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 Hnf1 alpha mRNAs underwent marked downregulation, matching endocrine/exocrine gene expression profiles. Ptf1a, Pdx1 and Hnf1 alpha 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 Hnf1 alpha gene and protein expression were recapitulated. Reduced Hnf1 alpha and Ptf1a levels after pancreatitis coincided with increased acinar cell proliferation, both in Hnf1 alpha(-/-) and Ptf1a(+/-) mice. Moreover, Hnf1 alpha(-/-) mice had reduced Ptf1a protein as well as transcripts for Ptf1a and digestive enzymes. Dispersed acini from Hnf1 alpha(-/-) mice showed suboptimal secretory responses to caerulein. Bioinformatics analysis did not support a role for Hnf1 alpha as a direct regulator of digestive enzyme genes. Instead, it was found that Hnf1 alpha 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 Hnf1 alpha in the regulation of acinar cell determination and function. This effect may be mediated, in part, through direct regulation of Nr5a2.