A new study shows that deficiency in pancreatic fibroblast growth factor 21 (FGF21) is a driving factor in acute and chronic pancreatitis in mice and humans. The new work also demonstrates that FGF21 treatment in various mouse models of pancreatitis alleviated symptoms and prevented onset of the disease, highlighting its clinical potential.

Credit: Lara Crow/Springer Nature Limited

The exocrine pancreas is a source of digestive enzymes that can cause tissue damage and inflammation known as pancreatitis when prematurely activated in the pancreas itself. The exocrine pancreas also expresses FGF21, where it stimulates digestive enzyme secretion by acinar cells. “This project was started based on previous work from our lab and others demonstrating that loss of FGF21 from the pancreas results in an increased susceptibility to acute pancreatitis in mice,” says lead author David Mangelsdorf.

The team’s previous work also found that FGF21 protection from pancreatitis was due to its ability to mitigate the integrated stress response (ISR) pathway, part of the unfolded protein response (UPR). “This is a key finding because acinar cells synthesize more protein than almost every other cell type in the body, so controlling the UPR is important,” explains Mangelsdorf.

In the latest work, using mouse models similar to human disease, including alcohol induced pancreatitis and post-endoscopic retrograde cholangiopancreatography pancreatitis, administration of FGF21 was shown to be effective in treating and preventing pancreatitis. In these mice, as well as samples from patients with acute and chronic pancreatitis, a loss of FGF21 expression was found in the pancreas. “This suggests that pancreatitis is a loss of FGF21 function disease and explains why FGF21 replacement therapy might be effective,” reports Mangelsdorf.

Using in vitro experiments, the mechanism of FGF21 loss was attributed to overactivation of the ISR pathway, which induced the expression of ATF3, a transcriptional suppressor of FGF21. Importantly, this mechanism was also confirmed in samples from patients with pancreatitis.

The researchers are now looking towards a clinical trial. “Our findings suggest a new therapeutic use of FGF21, which has already been used in clinical trials for other indications such as obesity,” says Mangelsdorf. “Notably, these other indications require chronic use of FGF21, whereas pancreatitis would be a more acute indication with implications for reducing potential adverse events associated with long-term FGF21 use.”