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Pancreatitis is an FGF21-deficient state that is corrected by replacement therapy

Repression of FGF21 by the integrated stress response contributes to pancreatitis and can be reversed with either stress response inhibitors or FGF21. Pancreatic stress management Pancreatitis results from the premature activation of digestive enzymes in the pancreas and can be potentially life threatening. Hernandez et al. found pancreatic fibroblast growth factor 21 (FGF21) deficiency in three mouse models and patient biopsies of acute and chronic pancreatitis. The authors showed that this deficiency resulted from the activation of the integrated stress response, and accordingly, both FGF21 administration and pharmacologic stress response inhibition restored FGF21 and alleviated symptoms in acute and chronic models of the disease. FGF21 treatment also prevented pancreatitis onset in a model of endoscopic retrograde cholangiopancreatography, a therapeutic procedure that carries pancreatitis risk. This study could have implications for the clinical management of pancreatitis. The exocrine pancreas expresses the highest concentrations of fibroblast growth factor 21 (FGF21) in the body, where it maintains acinar cell proteostasis. Here, we showed in both mice and humans that acute and chronic pancreatitis is associated with a loss of FGF21 expression due to activation of the integrated stress response (ISR) pathway. Mechanistically, we found that activation of the ISR in cultured acinar cells and mouse pancreata induced the expression of ATF3, a transcriptional repressor that directly bound to specific sites on the Fgf21 promoter and resulted in loss of FGF21 expression. These ATF3 binding sites are conserved in the human FGF21 promoter. Consistent with the mouse studies, we also observed the reciprocal expression of ATF3 and FGF21 in the pancreata of human patients with pancreatitis. Using three different mouse models of pancreatitis, we showed that pharmacologic replacement of FGF21 mitigated the ISR and resolved pancreatitis. Likewise, inhibition of the ISR with an inhibitor of the PKR-like endoplasmic reticulum kinase (PERK) also restored FGF21 expression and alleviated pancreatitis. These findings highlight the importance of FGF21 in preserving exocrine pancreas function and suggest its therapeutic use for prevention and treatment of pancreatitis.