title: FGF21 Is an Exocrine Pancreas Secretagogue.
abstract: 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.
authors.affiliation: Department of Pharmacology, UT Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Katie C
authors.initials: KC
authors.lastname: Coate
authors.affiliation: Department of Pharmacology, UT Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Genaro
authors.initials: G
authors.lastname: Hernandez
authors.affiliation: Department of Pharmacology, UT Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Curtis A
authors.initials: CA
authors.lastname: Thorne
authors.affiliation: Department of Pharmacology, UT Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Shengyi
authors.initials: S
authors.lastname: Sun
authors.affiliation: Department of Pharmacology, UT Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Thao D V
authors.initials: TDV
authors.lastname: Le
authors.affiliation: Department of Pharmacology, UT Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Kevin
authors.initials: K
authors.lastname: Vale
authors.affiliation: Department of Pharmacology, UT Southwestern Medical Center, Dallas, TX 75390, USA; Department of Molecular Biology, UT Southwestern Medical Center, Dallas, TX 75390, USA. Electronic address: steven.kliewer@utsouthwestern.edu.
authors.forename: Steven A
authors.initials: SA
authors.lastname: Kliewer
authors.affiliation: Department of Pharmacology, UT Southwestern Medical Center, Dallas, TX 75390, USA; Howard Hughes Medical Institute, UT Southwestern Medical Center, Dallas, TX 75390, USA. Electronic address: davo.mango@utsouthwestern.edu.
authors.forename: David J
authors.initials: DJ
authors.lastname: Mangelsdorf
mesh_terms: D000818:Animals; D019898:Autocrine Communication; D002118:Calcium / Q000378:metabolism; D004063:Digestion; D059865:Endoplasmic Reticulum Stress; D005346:Fibroblast Growth Factors / Q000378:metabolism*; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000378:metabolism; D042541:Intracellular Space / Q000378:metabolism; D008297:Male; D018345:Mice, Knockout; D046790:Pancreas, Exocrine / Q000201:enzymology / Q000378:metabolism*; D019899:Paracrine Communication; D051966:Phospholipase C gamma / Q000378:metabolism; D014176:Protein Biosynthesis; D017468:Receptors, Fibroblast Growth Factor / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D053496:Inositol 1,4,5-Trisphosphate Receptors; D017468:Receptors, Fibroblast Growth Factor; C414620:fibroblast growth factor 21; D005346:Fibroblast Growth Factors; D051966:Phospholipase C gamma; D002118:Calcium
keywords: CCK; FGF21; acinar cell; calcium signaling; exocrine pancreas; pancreatitis; proteostasis; secretagogue; secretion; β-Klotho