Fibroblast growth factor 21 reduces the severity of cerulein-induced pancreatitis in mice.
OBJECTIVE
Fibroblast 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.


METHODS
Fgf21 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(-/-)).


RESULTS
Acinar 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.


CONCLUSIONS
These studies suggest a novel function for Fgf21 as an immediate response gene protecting pancreatic acini from overt damage.
Johnson
Charis L
CL
Children's Health Research Institute, London, Ontario.
Weston
Jacqueline Y
JY
Chadi
Sami A
SA
Fazio
Elena N
EN
Huff
Murray W
MW
Kharitonenkov
Alexei
A
Köester
Anja
A
Pin
Christopher L
CL
D000818:Animals; D018929:Cell Culture Techniques; D002108:Ceruletide; D051766:Early Growth Response Protein 1 / Q000378:metabolism; D005346:Fibroblast Growth Factors / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D046790:Pancreas, Exocrine / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D010195:Pancreatitis / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017468:Receptors, Fibroblast Growth Factor / Q000378:metabolism
D051766:Early Growth Response Protein 1; C486109:Egr1 protein, mouse; D012333:RNA, Messenger; D017468:Receptors, Fibroblast Growth Factor; C414620:fibroblast growth factor 21; D005346:Fibroblast Growth Factors; D002108:Ceruletide