Activation of Pancreatic Acinar FXR Protects against Pancreatitis via Osgin1-Mediated Restoration of Efficient Autophagy release_ud7q5k2szvfr3bna2fbb3hkbmq [as of editgroup_c76fbwxdnzdhnmgmatybty7fni]

Abstract

Pancreatitis is the leading cause of hospitalization in gastroenterology, and no medications are available for treating this disease in current clinical practice. FXR plays an anti-inflammatory role in diverse inflammatory diseases, while its function in pancreatitis remains unknown. In this study, we initially observed a marked increase of nuclear FXR in pancreatic tissues of human patients with pancreatitis. Deleting the FXR in pancreatic acinar cells (FXR<jats:sup>acinar<jats:italic>Δ</jats:italic>/<jats:italic>Δ</jats:italic></jats:sup>) led to more severe pancreatitis in mouse models of caerulein-induced acute and chronic pancreatitis, while the FXR agonist GW4064 significantly attenuated pancreatitis in caerulein or arginine-induced acute pancreatitis and caerulein-induced chronic pancreatitis. FXR deletion impaired the viability and stress responses of pancreatic exocrine organoids (PEOs) in vitro. Utilizing RNA-seq and ChIP-seq of PEOs, we identified <jats:italic>Osgin</jats:italic>1 as a direct target of FXR in the exocrine pancreas, which was also increasingly expressed in human pancreatitis tissues compared to normal pancreatic tissues. Pancreatic knockdown of <jats:italic>Osgin</jats:italic>1 by AAV-pan abolished the therapeutic effects of FXR activation on pancreatitis, whereas pancreatic overexpression of <jats:italic>Osgin</jats:italic>1 effectively alleviated caerulein-induced pancreatitis. Mechanistically, we found that the FXR-OSGIN1 axis stimulated autophagic flux in the pancreatic tissues and cell lines, which was considered as the intrinsic mechanisms through which FXR-OSGIN1 protecting against pancreatitis. Our results highlight the protective role of the FXR-OSGIN1 axis in pancreatitis and provided a new target for the treatment of this disease.
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