Article

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

Children's Health Research Institute, London, Ontario.
Gastroenterology (Impact Factor: 13.93). 08/2009; 137(5):1795-804. DOI: 10.1053/j.gastro.2009.07.064
Source: PubMed

ABSTRACT 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.
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(-/-)).
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.
These studies suggest a novel function for Fgf21 as an immediate response gene protecting pancreatic acini from overt damage.

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    • "It is difficult to pinpoint the exact contributions that hepatic FGF-21 mRNA expression has on circulating FGF-21 levels (Zhang et al. 2008; Berglund et al. 2010). This is especially challenging as multiple tissues, including liver (Dushay et al. 2010; Fisher et al. 2010), adipose (Fisher et al. 2010), pancreas (Johnson et al. 2009), and possibly muscle (Izumiya et al. 2008), express FGF-21 and could contribute to circulating levels. Because FGF-21 has been shown to act in both a paracrine and endocrine fashion (Fisher et al. 2011), FGF-21 may target both local hepatocytes or may contribute to the FGF-21 serum concentrations. "
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    • "Thus, FGF21 is restricted to acting in an autocrine or paracrine manner in WAT, much like conventional FGFs. FGF21 is also proposed to act through an autocrine mechanism in exocrine pancreas and liver (Fisher et al., 2010; Johnson et al., 2009). In recent human studies, rosiglitazone treatment had no effect on circulating FGF21 concentrations in subjects who were either healthy or had impaired glucose tolerance (Christodoulides et al., 2009; Mai et al., 2009), but significantly decreased circulating FGF21 in patients with type 2 diabetes (Li et al., 2009a). "
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