FGF21 Is an Exocrine Pancreas Secretagogue.
FGF21 Is an Exocrine Pancreas Secretagogue.
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DOI：
10.1016/j.cmet.2016.12.004
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发表时间：
2017-02-07
期刊：
影响因子：
29
通讯作者：
Mangelsdorf DJ
中科院分区：
文献类型：
--
作者：
Coate KC;Hernandez G;Thorne CA;Sun S;Le TDV;Vale K;Kliewer SA;Mangelsdorf DJ
代谢应激激素FGF 21在外分泌胰腺中高度表达，其水平通过再喂养和化学诱导的胰腺炎而增加。然而，其在胰腺外分泌中的功能仍然未知。在这里，我们表明FGF 21通过自分泌/旁分泌机制刺激胰腺腺泡细胞的消化酶分泌，该机制需要通过由FGF受体和β-Klotho组成的酪氨酸激酶受体复合物进行信号传导。缺乏FGF 21的小鼠积累酶原颗粒，并且对胰腺ER应激敏感，这一效应可通过施用重组FGF 21逆转。携带β-Klotho腺泡细胞特异性缺失的小鼠也积累酶原颗粒，但对FGF 21刺激的分泌不敏感。与经典的餐后促分泌素胆囊收缩素（CCK）一样，FGF 21通过PLC-IP 3R信号传导触发细胞内钙释放。然而，与CCK不同，FGF 21不诱导蛋白质合成，从而防止蛋白质积累。因此，胰腺FGF 21是消化酶促分泌素，其生理功能是维持腺泡细胞蛋白质稳态。
The metabolic stress hormone FGF21 is highly expressed in exocrine pancreas, where its levels are increased by refeeding and chemically-induced pancreatitis. However, its function in the exocrine pancreas remains unknown. Here, we show that FGF21 stimulates digestive enzyme secretion from pancreatic acinar cells through an autocrine/paracrine mechanism that requires signaling through a tyrosine kinase receptor complex composed of an FGF receptor and β-Klotho. Mice lacking FGF21 accumulate zymogen granules and are susceptible to pancreatic ER stress, an effect that is reversed by administration of recombinant FGF21. Mice carrying an acinar cell-specific deletion of β-Klotho also accumulate zymogen granules, but are refractory to FGF21-stimulated secretion. Like the classical post-prandial secretagogue, cholecystokinin (CCK), FGF21 triggers intracellular calcium release via PLC-IP3R signaling. However, unlike CCK, FGF21 does not induce protein synthesis, thereby preventing protein accumulation. Thus, pancreatic FGF21 is a digestive enzyme secretagogue whose physiologic function is to maintain acinar cell proteostasis.