Milk Fat Globule Epidermal Growth Factor 8 Alleviates Liver Injury in Severe Acute Pancreatitis by Restoring Autophagy Flux and Inhibiting Ferroptosis in Hepatocytes

Overview

Journal World J Gastroenterol

Publisher Baishideng Publishing Group

Specialty Gastroenterology

Date 2024 Mar 22

PMID 38515944

Authors

Qing Cui

Hang-Cheng Liu

Wu-Ming Liu

Feng Ma

Yi Lv

Jian-Cang Ma

Rong-Qian Wu

Yi-Fan Ren

Affiliations

Soon will be listed here.

Abstract

Background: 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.

Aim: To speculate whether MFG-E8 could also alleviate SAP induced liver injury by restoring the abnormal autophagy flux.

Methods: 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.

Results: 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.

Conclusion: 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.

Citing Articles

The role of autophagy in pancreatic diseases.

Zhang W, Wu Q, Shao B Front Pharmacol. 2024; 15:1444657.

PMID: 39403146 PMC: 11471688. DOI: 10.3389/fphar.2024.1444657.

References

Capelletti M, Manceau H, Puy H, Peoch K . Ferroptosis in Liver Diseases: An Overview. Int J Mol Sci. 2020; 21(14). PMC: 7404091. DOI: 10.3390/ijms21144908. View

Lankisch P, Apte M, Banks P . Acute pancreatitis. Lancet. 2015; 386(9988):85-96. DOI: 10.1016/S0140-6736(14)60649-8. View

Jiang X, Stockwell B, Conrad M . Ferroptosis: mechanisms, biology and role in disease. Nat Rev Mol Cell Biol. 2021; 22(4):266-282. PMC: 8142022. DOI: 10.1038/s41580-020-00324-8. View

Liu Z, Ma C, Wang Q, Yang H, Lu Z, Bi T . Targeting FAM134B-mediated reticulophagy activates sorafenib-induced ferroptosis in hepatocellular carcinoma. Biochem Biophys Res Commun. 2021; 589:247-253. DOI: 10.1016/j.bbrc.2021.12.019. View

Tang D, Chen X, Kang R, Kroemer G . Ferroptosis: molecular mechanisms and health implications. Cell Res. 2020; 31(2):107-125. PMC: 8026611. DOI: 10.1038/s41422-020-00441-1. View

Ren Y, Liu W, Zhang J, Bi J, Fan M, Lv Y . MFG-E8 Maintains Cellular Homeostasis by Suppressing Endoplasmic Reticulum Stress in Pancreatic Exocrine Acinar Cells. Front Cell Dev Biol. 2022; 9:803876. PMC: 8795834. DOI: 10.3389/fcell.2021.803876. View

An S, Jang Y, Lim H, Han J, Lee J, Lee G . Milk Fat Globule-EGF Factor 8, Secreted by Mesenchymal Stem Cells, Protects Against Liver Fibrosis in Mice. Gastroenterology. 2016; 152(5):1174-1186. DOI: 10.1053/j.gastro.2016.12.003. View

Aziz M, Yang W, Corbo L, Chaung W, Matsuo S, Wang P . MFG-E8 inhibits neutrophil migration through αvβ₃-integrin-dependent MAP kinase activation. Int J Mol Med. 2015; 36(1):18-28. PMC: 4494603. DOI: 10.3892/ijmm.2015.2196. View

Ren Y, Liu W, Zhang J, Bi J, Wang T, Wang M . Milk fat globule EGF factor 8 restores mitochondrial function via integrin-medicated activation of the FAK-STAT3 signaling pathway in acute pancreatitis. Clin Transl Med. 2021; 11(2):e295. PMC: 7828261. DOI: 10.1002/ctm2.295. View

10.

Saitoh T, Fujita N, Jang M, Uematsu S, Yang B, Satoh T . Loss of the autophagy protein Atg16L1 enhances endotoxin-induced IL-1beta production. Nature. 2008; 456(7219):264-8. DOI: 10.1038/nature07383. View

11.

Hanayama R, Tanaka M, Miwa K, Shinohara A, Iwamatsu A, Nagata S . Identification of a factor that links apoptotic cells to phagocytes. Nature. 2002; 417(6885):182-7. DOI: 10.1038/417182a. View

12.

Li Y, Gao Q, Shu X, Xiao L, Yang Y, Pang N . Antagonizing αvβ3 Integrin Improves Ischemia-Mediated Vascular Normalization and Blood Perfusion by Altering Macrophages. Front Pharmacol. 2021; 12:585778. PMC: 7944575. DOI: 10.3389/fphar.2021.585778. View

13.

Miksa M, Amin D, Wu R, Jacob A, Zhou M, Dong W . Maturation-induced down-regulation of MFG-E8 impairs apoptotic cell clearance and enhances endotoxin response. Int J Mol Med. 2008; 22(6):743-8. PMC: 2787083. View

14.

Habtezion A, Gukovskaya A, Pandol S . Acute Pancreatitis: A Multifaceted Set of Organelle and Cellular Interactions. Gastroenterology. 2019; 156(7):1941-1950. PMC: 6613790. DOI: 10.1053/j.gastro.2018.11.082. View

15.

Levine B, Kroemer G . Biological Functions of Autophagy Genes: A Disease Perspective. Cell. 2019; 176(1-2):11-42. PMC: 6347410. DOI: 10.1016/j.cell.2018.09.048. View

16.

Zhao C, Yu D, He Z, Bao L, Feng L, Chen L . Endoplasmic reticulum stress-mediated autophagy activation is involved in cadmium-induced ferroptosis of renal tubular epithelial cells. Free Radic Biol Med. 2021; 175:236-248. DOI: 10.1016/j.freeradbiomed.2021.09.008. View

17.

Cadwell K, Liu J, Brown S, Miyoshi H, Loh J, Lennerz J . A key role for autophagy and the autophagy gene Atg16l1 in mouse and human intestinal Paneth cells. Nature. 2008; 456(7219):259-63. PMC: 2695978. DOI: 10.1038/nature07416. View

18.

Banks P, Bollen T, Dervenis C, Gooszen H, Johnson C, Sarr M . Classification of acute pancreatitis--2012: revision of the Atlanta classification and definitions by international consensus. Gut. 2012; 62(1):102-11. DOI: 10.1136/gutjnl-2012-302779. View

19.

Zhang Z, Guo M, Li Y, Shen M, Kong D, Shao J . RNA-binding protein ZFP36/TTP protects against ferroptosis by regulating autophagy signaling pathway in hepatic stellate cells. Autophagy. 2019; 16(8):1482-1505. PMC: 7469536. DOI: 10.1080/15548627.2019.1687985. View

20.

Lee P, Papachristou G . New insights into acute pancreatitis. Nat Rev Gastroenterol Hepatol. 2019; 16(8):479-496. DOI: 10.1038/s41575-019-0158-2. View