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Background & AimsFibroblast growth factor 21 (FGF21) acts as a hormonal regulator during fasting and is involved in lipid metabolism. Fgf21 gene expression is regulated by peroxisome proliferator-activated receptor (PPAR)-dependent pathways, which are enhanced during pancreatitis. Therefore, the aim of this study was to investigate FGF21's role in pancreatic injury. MethodsFgf21 expression was quantified during cerulein-induced pancreatitis (CIP) or following mechanical or thapsigargin-induced stress through Northern blot analysis, in situ hybridization, and quantitative reverse transcription polymerase chain reaction. FGF21 protein was quantified by Western blot analysis. Isolated acinar cells or AR42J acinar cells were treated with recombinant FGF21 protein, and extracellular regulated kinase 1/2 activation was examined. The severity of CIP was compared between wild-type mice and mice overexpressing FGF21 (FGF21Tg) or harboring a targeted deletion of Fgf21 (Fgf21−/−). ResultsAcinar cell Fgf21 expression markedly increased during CIP and following injury in vitro. Purified FGF21 activated the extracellular regulated kinase 1/2 pathway in pancreatic acinar cells. The severity of CIP is inversely correlated to FGF21 expression because FGF21Tg mice exhibited decreased serum amylase and decreased pancreatic stellate cell activation, whereas Fgf21−/− mice had increased serum amylase and tissue damage. The expression of Fgf21 was also inversely correlated to expression of Early growth response 1, a proinflammatory and profibrotic transcription factor. ConclusionsThese studies suggest a novel function for Fgf21 as an immediate response gene protecting pancreatic acini from overt damage. Abbreviations used in this paper: CCK, cholecystokinin, CIP, cerulein-induced pancreatitis, CPA, carboxypeptidase, PDGF, platelet-derived growth factor, EGR-1, Early growth response 1, ERK1/2, extracellular regulated kinase 1/2, IL-6, interleukin 6, JNK, Jun N-terminal kinase, PPAR, peroxisome proliferator-activated receptor, PSC, pancreatic stellate cells, SMA, smooth muscle actin, WT, wild type ⁎ Children's Health Research Institute, London, Ontario ‡ Department of Physiology & Pharmacology, The University of Western Ontario, London, Ontario § Department of Paediatrics, The University of Western Ontario, London, Ontario ∥ Department of Biochemistry, The University of Western Ontario, London, Ontario ¶ Lilly Research Laboratories, Division of Eli Lilly, Indianapolis, Indiana
Conflicts of interest The authors disclose no conflicts. Funding Supported by operating grants from the Canadian Institutes of Health Research (CIHR; CP-MOP 53083), Children's Health Research Institute, and Lawson Health Research Institute; by an Ontario Graduate Scholarship for Science and Technology (to J.W.); and by a New Investigator Award from the CIHR (to C.P.). PII: S0016-5085(09)01389-4 doi:10.1053/j.gastro.2009.07.064 © 2009 AGA Institute. Published by Elsevier Inc. All rights reserved.
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ABSTRACT
Fibroblast Growth Factor 21 Reduces the Severity of Cerulein-Induced Pancreatitis in Mice