Fibroblast Growth Factor 21 Reduces the Severity of Cerulein-Induced Pancreatitis in Mice
Fibroblast Growth Factor 21 Reduces the Severity of Cerulein-Induced Pancreatitis in Mice
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DOI：
10.1053/j.gastro.2009.07.064
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发表时间：
2009-11-01
期刊：
影响因子：
29.4
通讯作者：
Pin, Christopher L.
中科院分区：
文献类型：
--
作者：
Johnson, Charis L.;Weston, Jacqueline Y.;Pin, Christopher L.
背景与目的：成纤维细胞生长因子21 （FGF21）在禁食期间作为激素调节因子，参与脂质代谢。Fgf21基因表达受过氧化物酶体增殖物激活受体（PPAR）依赖通路调控，该通路在胰腺炎期间增强。因此，本研究的目的是探讨FGF21在胰腺损伤中的作用。方法：通过Northern blot分析、原位杂交和定量逆转录聚合酶链反应，定量检测蛋白诱导胰腺炎（CIP）或机械性或thapsigargin诱导应激时Fgf21的表达。Western blot检测FGF21蛋白含量。用重组FGF21蛋白处理分离的腺泡细胞或AR42J腺泡细胞，观察细胞外调节激酶1/2的活化情况。比较野生型小鼠与过表达FGF21 （FGF21Tg）或FGF21靶向缺失（FGF21(-/-)）小鼠之间CIP的严重程度。结果：腺泡细胞Fgf21表达明显升高。在体外CIP期间和损伤后。纯化的FGF21激活胰腺腺泡细胞胞外调节激酶1/2通路。CIP的严重程度与FGF21的表达呈负相关，因为FGF21Tg小鼠表现出血清淀粉酶降低和胰腺星状细胞活化降低，而FGF21（-/-）小鼠表现出血清淀粉酶增加和组织损伤。Fgf21的表达也与促炎和促纤维化转录因子Early growth response 1的表达呈负相关。结论：这些研究表明Fgf21作为一种即时反应基因具有新的功能，可以保护胰腺腺泡免受明显损伤。
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.