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

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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 via binding to αvβ3/5 integrins. MFG-E8 also seems to mitigate pancreatic fibrosis via 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. mfge8-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.

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Most cited references 56

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Ferroptosis: mechanisms, biology and role in disease

Xuejun Jiang, Brent Stockwell, Marcus Conrad (2021)

The research field of ferroptosis has seen exponential growth over the past few years, since the term was coined in 2012. This unique modality of cell death, driven by iron-dependent phospholipid peroxidation, is regulated by multiple cellular metabolic pathways, including redox homeostasis, iron handling, mitochondrial activity and metabolism of amino acids, lipids and sugars, in addition to various signalling pathways relevant to disease. Numerous organ injuries and degenerative pathologies are driven by ferroptosis. Intriguingly, therapy-resistant cancer cells, particularly those in the mesenchymal state and prone to metastasis, are exquisitely vulnerable to ferroptosis. As such, pharmacological modulation of ferroptosis, via both its induction and its inhibition, holds great potential for the treatment of drug-resistant cancers, ischaemic organ injuries and other degenerative diseases linked to extensive lipid peroxidation. In this Review, we provide a critical analysis of the current molecular mechanisms and regulatory networks of ferroptosis, the potential physiological functions of ferroptosis in tumour suppression and immune surveillance, and its pathological roles, together with a potential for therapeutic targeting. Importantly, as in all rapidly evolving research areas, challenges exist due to misconceptions and inappropriate experimental methods. This Review also aims to address these issues and to provide practical guidelines for enhancing reproducibility and reliability in studies of ferroptosis. Finally, we discuss important concepts and pressing questions that should be the focus of future ferroptosis research.

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The CoQ oxidoreductase FSP1 acts in parallel to GPX4 to inhibit ferroptosis

Kirill Bersuker, Joseph Hendricks, Zhipeng Li … (2019)

Ferroptosis is a form of regulated cell death that is caused by the iron-dependent peroxidation of lipids 1,2 . The glutathione-dependent lipid hydroperoxidase glutathione peroxidase 4 (GPX4) prevents ferroptosis by converting lipid hydroperoxides into non-toxic lipid alcohols 3,4 . Ferroptosis has been implicated in the cell death that underlies several degenerative conditions 2 , and induction of ferroptosis by inhibition of GPX4 has emerged as a therapeutic strategy to trigger cancer cell death 5 . However, sensitivity to GPX4 inhibitors varies greatly across cancer cell lines 6 , suggesting that additional factors govern resistance to ferroptosis. Here, employing a synthetic lethal CRISPR/Cas9 screen, we identify ferroptosis suppressor protein 1 (FSP1) (previously known as apoptosis-inducing factor mitochondrial 2 (AIFM2)) as a potent ferroptosis resistance factor. Our data indicate that myristoylation recruits FSP1 to the plasma membrane where it functions as an oxidoreductase that reduces coenzyme Q10 (CoQ), generating a lipophilic radical-trapping antioxidant (RTA) that halts the propagation of lipid peroxides. We further find that FSP1 expression positively correlates with ferroptosis resistance across hundreds of cancer cell lines, and that FSP1 mediates resistance to ferroptosis in lung cancer cells in culture and in mouse tumor xenografts. Thus, our data identify FSP1 as a key component of a non-mitochondrial CoQ antioxidant system that acts in parallel to the canonical glutathione-based GPX4 pathway. These findings define a new ferroptosis suppression pathway and indicate that pharmacological inhibition of FSP1 may provide an effective strategy to sensitize cancer cells to ferroptosis-inducing chemotherapeutics.

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Classification of acute pancreatitis--2012: revision of the Atlanta classification and definitions by international consensus.

Peter A Banks, Thomas Bollen, CHRISTOS DERVENIS … (2012)

The Atlanta classification of acute pancreatitis enabled standardised reporting of research and aided communication between clinicians. Deficiencies identified and improved understanding of the disease make a revision necessary. A web-based consultation was undertaken in 2007 to ensure wide participation of pancreatologists. After an initial meeting, the Working Group sent a draft document to 11 national and international pancreatic associations. This working draft was forwarded to all members. Revisions were made in response to comments, and the web-based consultation was repeated three times. The final consensus was reviewed, and only statements based on published evidence were retained. The revised classification of acute pancreatitis identified two phases of the disease: early and late. Severity is classified as mild, moderate or severe. Mild acute pancreatitis, the most common form, has no organ failure, local or systemic complications and usually resolves in the first week. Moderately severe acute pancreatitis is defined by the presence of transient organ failure, local complications or exacerbation of co-morbid disease. Severe acute pancreatitis is defined by persistent organ failure, that is, organ failure >48 h. Local complications are peripancreatic fluid collections, pancreatic and peripancreatic necrosis (sterile or infected), pseudocyst and walled-off necrosis (sterile or infected). We present a standardised template for reporting CT images. This international, web-based consensus provides clear definitions to classify acute pancreatitis using easily identified clinical and radiologic criteria. The wide consultation among pancreatologists to reach this consensus should encourage widespread adoption.

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Author and article information

Contributors

Qing Cui

Hang-Cheng Liu

Wu-Ming Liu

Feng Ma

Yi Lv

Jian-Cang Ma

Rong-Qian Wu

Yi-Fan Ren

Journal

Journal ID (nlm-ta): World J Gastroenterol

Journal ID (iso-abbrev): World J Gastroenterol

Journal ID (publisher-id): WJG

Title: World Journal of Gastroenterology

Publisher: Baishideng Publishing Group Inc

ISSN (Print): 1007-9327

ISSN (Electronic): 2219-2840

Publication date (Print): 21 February 2024

Publication date (Electronic): 21 February 2024

Volume: 30

Issue: 7

Pages: 728-741

Affiliations

Department of Cardiology, Xi’an Central Hospital Affiliated to Xi’an Jiaotong University, Xi’an 710003, Shaanxi Province, China

Department of General Surgery, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710004, Shaanxi Province, China

National Local Joint Engineering Research Center for Precision Surgery & Regenerative Medicine, Shaanxi Provincial Center for Regenerative Medicine and Surgical Engineering, First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, Shaanxi Province, China

Department of Hepatobiliary Surgery, First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, Shaanxi Province, China

Department of Cardiology, Xi’an Central Hospital Affiliated to Xi’an Jiaotong University, Xi’an 710003, Shaanxi Province, China

Department of Hepatobiliary Surgery, First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, Shaanxi Province, China

Department of Vascular Surgery, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710004, Shaanxi Province, China

Department of General Surgery, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710004, Shaanxi Province, China

Author notes

Co-first authors: Qing Cui and Hang-Cheng Liu.

Author contributions: Cui Q, Liu HC, and Liu WM acquired and analyzed the data, wrote the paper; Ma F, Lv Y, Ma JC, and Wu RQ interpreted the data; Lv Y, Wu RQ, and Ren YF revised the paper; Ren YF designed and supervised the study; and all authors approved the final version of the article.

Supported by the National Natural Science Foundation of China, No. 82100685; the Scientific Research Fund of Xi’an Health Commission, No. 2021yb08; Scientific Research Fund of Xi’an Central Hospital, No. 2022QN07; and Innovation Capability Support Plan of Xi’an Science and Technology Bureau, No. 23YXYJ0097.

Corresponding author: Yi-Fan Ren, MD, PhD, Assistant Professor, Surgeon, Department of General Surgery, The Second Affiliated Hospital of Xi’an Jiaotong University, No. 157 West Fifth Road, Xi’an 710004, Shaanxi Province, China. 871396704@ 123456qq.com

Article

Other ID: jWJG.v30.i7.pg728 Publisher-manuscript ID: 88932

DOI: 10.3748/wjg.v30.i7.728

PMC ID: 10950629

PubMed ID: 38515944

SO-VID: a8057542-e152-444f-849c-2b6e36b086af

License:

This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial.

History

Date received : 21 October 2023

Date revision received : 18 December 2023

Date accepted : 15 January 2024

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

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Abstract

BACKGROUND

AIM

METHODS

RESULTS

CONCLUSION

Related collections

GLUT4 biology

Most cited references 56

Ferroptosis: mechanisms, biology and role in disease

The CoQ oxidoreductase FSP1 acts in parallel to GPX4 to inhibit ferroptosis

Classification of acute pancreatitis--2012: revision of the Atlanta classification and definitions by international consensus.

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Contributors

Journal

Affiliations

Author notes

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History

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