The Physiology and Pharmacology of FGF21 in the Exocrine Pancreas




Hernandez, Genaro

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The exocrine pancreas comprises about 98% of the total pancreatic tissue. Its main function is the synthesis and secretion of digestive enzymes in order to facilitate nutrient absorption upon feeding. This function is mainly carried by acinar cells that require strict regulation of protein processing and stress-related pathways such as the integrated stress response pathway (ISR). Genetic, chemical or traumatic events can trigger an inflammatory response in the pancreas known as pancreatitis with prolonged ISR activation. In the pancreas, fibroblast growth factor 21 (FGF21) is highly expressed, induced by feeding and acts in an autocrine/paracrine fashion. The pancreas also expresses the FGFR1/beta-klotho receptor complex that FGF21 binds to elicit downstream signaling. The physiological function of FGF21 in the exocrine pancreas is to stimulate digestive enzyme secretion by triggering intracellular calcium release through FGFR1/beta-klotho-PLCgamma-IP3R; without affecting protein synthesis on acinar cells. The effect of FGF21 on secretion results in lower levels of ISR activation by decreasing intracellular protein load. However, endogenous FGF21 is downregulated in pancreatitis, which leads to increased inflammation and overall pancreatic damage. Given that pancreatitis is an FGF21-deficient state, it can be ameliorated by therapeutically administering recombinant FGF21. Furthermore, the therapeutic effect of FGF21 is dependent on the expression of beta-klotho in acinar cells. The cause of this FGF21 deficit is the competitive binding of the transcriptional repressor ATF3 that displaces the FGF21-inducing transcription factor ATF4 from the AARE1 response element in the FGF21 promoter of acinar cells. Since ATF3 is induced by ISR activation in pancreatitis, therapeutic inhibition of the ISR is also effective but requires endogenous FGF21. Moreover, FGF21 is therapeutically effective in different types of pancreatitis such as alcohol-induced pancreatitis or endoscopic retrograde cholangiopancreatography-induced pancreatitis. These findings are supported by evidence that in patients with pancreatitis FGF21 and ATF4 are lost, whereas ATF3 is upregulated. Thus, under physiological conditions such as feeding FGF21 maintains protein homeostasis by acting as an autocrine/paracrine secretagogue but it is downregulated in pancreatitis. Pharmacologically, FGF21 is a promising drug candidate for the treatment of pancreatitis.

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