Coate Katie C, Hernandez Genaro, Thorne Curtis A, Sun Shengyi, Le Thao D V, Vale Kevin, Kliewer Steven A, Mangelsdorf David J
Department of Pharmacology, UT Southwestern Medical Center, Dallas, TX 75390, USA.
Department of Pharmacology, UT Southwestern Medical Center, Dallas, TX 75390, USA; Department of Molecular Biology, UT Southwestern Medical Center, Dallas, TX 75390, USA.
Cell Metab. 2017 Feb 7;25(2):472-480. doi: 10.1016/j.cmet.2016.12.004. Epub 2017 Jan 12.
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-IPR 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.
代谢应激激素FGF21在外分泌胰腺中高度表达，在重新进食和化学诱导的胰腺炎时其水平会升高。然而，它在外分泌胰腺中的功能仍然未知。在此，我们表明FGF21通过一种自分泌/旁分泌机制刺激胰腺腺泡细胞分泌消化酶，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FGF21的小鼠会积累酶原颗粒，并且易患胰腺内质网应激，给予重组FGF21可逆转这种效应。携带腺泡细胞特异性β-klotho缺失的小鼠也会积累酶原颗粒，但对FGF21刺激的分泌无反应。与经典的餐后促分泌素胆囊收缩素（CCK）一样，FGF21通过PLC-IPR信号传导触发细胞内钙释放。然而，与CCK不同的是，FGF21不会诱导蛋白质合成，从而防止蛋白质积累。因此，胰腺FGF21是一种消化酶促分泌素，其生理功能是维持腺泡细胞蛋白质稳态。
