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

Children's Health Research Institute, London, Ontario.
Gastroenterology (Impact Factor: 16.72). 08/2009; 137(5):1795-804. DOI: 10.1053/j.gastro.2009.07.064
Source: PubMed


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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Available from: Alexei Kharitonenkov
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    • "In addition to the beneficial pharmacological effects of exogenous FGF21, endogenous FGF21 also plays an important role in the maintenance of energy homeostasis in several stressful conditions, such as nutrient starvation [20,21] and cold exposure [22,23]. Furthermore, a growing body of research suggests that FGF21 is also able to exert protective functions in pathological conditions that occurring after the administration of chemicals, such as acetaminophen-induced liver toxicity [24], dioxin-induced toxicity [25], cerulein-induced pancreatitis [26], and phenylephrine-induced cardiac hypertrophic damage [27]. These findings suggest that FGF21 acts as a key regulator in the adaptation to stress and can limit the progression of stress in diverse disease conditions. "
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    • "In addition, secreted FGF21 may also function in an endocrine manner targeting the brain to regulate reproductive behavior, appetite and locomotor activity (Bookout et al., 2013; Owen et al., 2013). Production of FGF21 has subsequently been detected in multiple systemic tissues, including pancreas, brown adipose tissue (BAT), skeletal and cardiac muscle (Hondares et al., 2011; Johnson et al., 2009; Planavila et al., 2013), and appears to have a variety of additional physiological functions. For example, cold-exposure increases FGF21 production in BAT (Chartoumpekis et al., 2011; Hondares et al., 2011) where it stimulates the expression of several thermogenic genes (Fisher et al., 2012). "
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    • "Key to understanding the mechanisms behind FGF21 pharmacology was appreciation of the role of the endogenous FGF21 system that began with delineating tissues which either expressed or were capable of responding to this protein. As stated earlier FGF21 was identified in the liver [7], however, further expression was subsequently reported in white adipose tissue [68], brown adipose tissue [69], muscle [13] and pancreas [70]. In 2010 Dushay et al. published the first report on FGF21 expression in human liver and its elevation in subjects with non-alcoholic fatty liver disease (NAFLD) [71]. "
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