Milk fat globule epidermal growth factor 8 alleviates liver injury in severe acute pancreatitis by restoring autophagy flux and inhibiting ferroptosis in hepatocytes

• Published in: World journal of gastroenterology : WJG 2024-02, Vol.30 (7), p.728-741
• Main Authors: Cui, Qing, Liu, Hang-Cheng, Liu, Wu-Ming, Ma, Feng, Lv, Yi, Ma, Jian-Cang, Wu, Rong-Qian, Ren, Yi-Fan
• Format: Article
• Language: English
• Subjects: Acute Disease; Animals; Autophagy; Basic Study; Chemical and Drug Induced Liver Injury, Chronic; EGF Family of Proteins; Factor VIII; Ferroptosis; Glycolipids; Glycoproteins; Hepatocytes - metabolism; Lipid Droplets; Mice; Milk Proteins - metabolism; Milk Proteins - pharmacology; Pancreatitis - chemically induced; Pancreatitis - complications
• ISSN: 1007-9327; 2219-2840; 2219-2840
• DOI: 10.3748/wjg.v30.i7.728

Liver injury is common in severe acute pancreatitis (SAP). Excessive autophagy often leads to an imbalance of homeostasis in hepatocytes, which induces lipid peroxidation and mitochondrial iron deposition and ultimately leads to ferroptosis. Our previous study found that milk fat globule epidermal growth factor 8 (MFG-E8) alleviates acinar cell damage during SAP binding to αvβ3/5 integrins. MFG-E8 also seems to mitigate pancreatic fibrosis inhibiting chaperone-mediated autophagy. To speculate whether MFG-E8 could also alleviate SAP induced liver injury by restoring the abnormal autophagy flux. SAP was induced in mice by 2 hly intraperitoneal injections of 4.0 g/kg L-arginine or 7 hly injections of 50 μg/kg cerulein plus lipopolysaccharide. -knockout mice were used to study the effect of MFG-E8 deficiency on SAP-induced liver injury. Cilengitide, a specific αvβ3/5 integrin inhibitor, was used to investigate the possible mechanism of MFG-E8. The results showed that MFG-E8 deficiency aggravated SAP-induced liver injury in mice, enhanced autophagy flux in hepatocyte, and worsened the degree of ferroptosis. Exogenous MFG-E8 reduced SAP-induced liver injury in a dose-dependent manner. Mechanistically, MFG-E8 mitigated excessive autophagy and inhibited ferroptosis in liver cells. Cilengitide abolished MFG-E8's beneficial effects in SAP-induced liver injury. MFG-E8 acts as an endogenous protective mediator in SAP-induced liver injury. MFG-E8 alleviates the excessive autophagy and inhibits ferroptosis in hepatocytes by binding to integrin αVβ3/5.