Selenium corrects dysregulated mitophagy and lipophagy in obesity-related acute pancreatitis through the GPX1-Mfn2-PLIN2 axis

Abstract

The incidence of acute pancreatitis (AP) has been on the rise in recent years. Obesity, a significant contributor to AP, increases the risk of AP and promotes disease progression, leading to adverse outcomes. Mitophagy and lipophagy are two main types of selective autophagy in AP and obesity, but their contribution to comorbidity in obesity-related AP (OB-AP) remains unknown. This study demonstrated that OB-AP exhibited more severe pancreatic injury than AP in vivo and in vitro. We found that the balance between mitophagy and lipophagy was disrupted, with a significant increase in mitophagy and a corresponding significant decrease in lipophagy. Mechanistically, overexpression of selenoprotein glutathione peroxidase 1 (GPX1) stabilized mitofusin 2 (Mfn2) protein, promoting the interaction between Mfn2 and perilipin 2 (PLIN2), and thereby attenuating excessive mitophagy and increasing lipophagy. Selenium supplementation improved pancreatic autophagy homeostasis in OB-AP through increasing GPX1 expression, thereby reducing disease severity. Notably, OB-AP patients exhibited lower selenium levels than healthy individuals. In conclusion, selenium supplementation enhanced GPX1 expression, corrected the imbalance between mitophagy and lipophagy, and mitigated disease severity in OB-AP through the GPX1-Mfn2-PLIN2 axis, and therefore has therapeutic potential in OB-AP.