Depletion of Igfbp7 alleviates zebrafish NAFLD progression through inhibiting hepatic ferroptosis

Yanqin Wang; Jiaqi Bo; Zhonghua Zhao; Yuhang Han; Qianqian Zhang; Lixin Liu

doi:10.1016/j.lfs.2023.122086

Depletion of Igfbp7 alleviates zebrafish NAFLD progression through inhibiting hepatic ferroptosis

Life Sci. 2023 Nov 1:332:122086. doi: 10.1016/j.lfs.2023.122086. Epub 2023 Sep 14.

Authors

Yanqin Wang¹, Jiaqi Bo¹, Zhonghua Zhao², Yuhang Han¹, Qianqian Zhang³, Lixin Liu⁴

Affiliations

¹ Department of Gastroenterology and Hepatology, The First Hospital of Shanxi Medical University, Taiyuan 030001, China.
² Institutes of Biomedical Sciences, 1331 Local Bio-Resources and Health Industry Collaborative Innovation Center of Shanxi Province, Shanxi University, Taiyuan 030006, China.
³ Department of Gastroenterology and Hepatology, The First Hospital of Shanxi Medical University, Taiyuan 030001, China; Experimental Center of Science and Research, The First Hospital of Shanxi Medical University, Taiyuan 030001, China; Key Laboratory of Prevention and Treatment of Liver Injury and Digestive System Neoplasms, Provincial Committee of the Medical and Health, Taiyuan 030001, China.
⁴ Department of Gastroenterology and Hepatology, The First Hospital of Shanxi Medical University, Taiyuan 030001, China; Experimental Center of Science and Research, The First Hospital of Shanxi Medical University, Taiyuan 030001, China; Key Laboratory of Prevention and Treatment of Liver Injury and Digestive System Neoplasms, Provincial Committee of the Medical and Health, Taiyuan 030001, China. Electronic address: lixinliu6@sxmu.edu.cn.

PMID: 37714372
DOI: 10.1016/j.lfs.2023.122086

Abstract

Aims: The global increased expression of Insulin-like growth factor binding protein 7 (IGFBP7) has been detected in non-alcoholic fatty liver disease (NAFLD) patients, however, its roles in NAFLD and the mechanism remain largely unclear. The goal of this study is to investigate the effect and mechanism of Igfbp7 using a zebrafish NAFLD model.

Main methods: The igfbp7^-/- null zebrafish mutant and the Igfbp7 liver overexpressed (LOE) transgenic zebrafish based on Gal4/UAS system were generated by CRISPR/Cas9 and Tol2 transgenic technique, respectively. The zebrafish NAFLD models in wildtypes, igfbp7^-/- mutants and Igfbp7 LOE fishes have been established by high-fat diet feeding. The Igfbp7 dynamic expression and its effects on NAFLD progression have been detected and analyzed in both human NAFLD patients and zebrafish models. And the potential mechanism has been investigated through transcriptome analysis and subsequent detection and verification.

Key findings: High Igfbp7 levels in NASH and fibrosis stages have been detected in liver tissues of both human NAFLD patients and zebrafish models. Depletion of Igfbp7 significantly alleviated liver steatosis, inflammation, and fibrosis, whereas liver specific Igfbp7 overexpression dramatically exacerbated liver fibrosis in zebrafish NAFLD model. The hepatic iron deposition, lipid peroxidation products, and ferroptosis-related index were also significantly reduced at the NASH stage in the absence of Igfbp7. Igfbp7 promotes NAFLD progression through regulating ferroptosis, and Ncoa4-mediated ferritinophagy may be the pathway of Igfbp7-regulated ferroptosis.

Significance: Igfbp7 is confirmed as an important regulator in NAFLD progression. Depleting Igfbp7 effectively alleviates zebrafish NAFLD progression by inhibiting hepatic ferroptosis, suggesting a novel potential target for NAFLD treatment.

Keywords: Ferritinophagy; Ferroptosis; Igfbp7; NAFLD; Zebrafish NAFLD model.

MeSH terms

Animals
Diet, High-Fat
Ferroptosis*
Humans
Insulin-Like Growth Factor Binding Proteins* / genetics
Liver / metabolism
Liver Cirrhosis / pathology
Non-alcoholic Fatty Liver Disease* / metabolism
Zebrafish

Substances

insulin-like growth factor binding protein-related protein 1
Insulin-Like Growth Factor Binding Proteins