Title

Fibroblast Growth Factor 21 Reduces the Severity of Cerulein-Induced Pancreatitis in Mice

Authors

Charis L. Johnson, The University of Western Ontario
Jacqueline Y. Weston, The University of Western Ontario
Sami A. Chadi, The University of Western Ontario
Elena N. Fazio, The University of Western Ontario
Murray W. Huff, The University of Western Ontario
Alexei Kharitonenkov, Lilly Research Laboratories, Indianapolis, IN
Anja Köester, Lilly Research Laboratories, Indianapolis, IN
Christopher L. Pin, The University of Western Ontario

Document Type

Article

Publication Date

11-2009

Journal

Gastroenterology

Volume

137

Issue

5

First Page

1795

Last Page

1804

URL with Digital Object Identifier

http://dx.doi.org/10.1053/j.gastro.2009.07.064

Abstract

BACKGROUND & AIMS: 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.