Caveolin-1 is critical for hepatic iron storage capacity in the development of nonalcoholic fatty liver disease

Guang-Hui DENG, Chao-Feng WU, Yun-Jia LI, Hao SHI, Wei-Chao ZHONG, Mu-Keng HONG, Jun-Jie LI, Jia-Min ZHAO, Chang LIU, Meng-Chen QIN, Zhi-Yun ZENG, Wei-Min ZHANG, Kin Lam Ken YUNG, Zhi-Ping LV, Lei GAO

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Abstract

Background: Nonalcoholic fatty liver disease (NAFLD) is associated with disordered lipid and iron metabolism. Our previous study has substantiated the pivotal role of Caveolin-1 (Cav-1) in protecting hepatocytes and mediating iron metabolism in the liver. This study aimed to explore the specific mechanisms underlying the regulation of iron metabolism by Cav-1 in NAFLD. 

Methods: Hepatocyte-specific Cav-1 overexpression mice and knockout mice were used in this study. Cav-1-knockdown of RAW264.7 cells and mouse primary hepatocytes were performed to verify the changes in vitro. Moreover, a high-fat diet and palmitic acid plus oleic acid treatment were utilized to construct a NAFLD model in vivo and in vitro, respectively, while a high-iron diet was used to construct an in vivo iron overload model. Besides, iron concentration, the expression of Cav-1 and iron metabolism-related proteins in liver tissue or serum were detected using iron assay kit, Prussian blue staining, Western blotting, immunofluorescence staining, immunohistochemical staining and ELISA. The related indicators of lipid metabolism and oxidative stress were evaluated by the corresponding reagent kit and staining. 

Results: Significant disorder of lipid and iron metabolism occurred in NAFLD. The expression of Cav-1 was decreased in NAFLD hepatocytes (P < 0.05), accompanied by iron metabolism disorder. Cav-1 enhanced the iron storage capacity of hepatocytes by activating the ferritin light chain/ferritin heavy chain pathway in NAFLD, subsequently alleviating the oxidative stress induced by excess ferrous ions in the liver. Further, CD68+CD163+ macrophages expressing Cav-1 were found to accelerate iron accumulation in the liver, which was contrary to the effect of Cav-1 in hepatocytes. Positive correlations were also observed between the serum Cav-1 concentration and the serum iron-related protein levels in NAFLD patients and healthy volunteers (P < 0.05). 

Conclusions: These findings confirm that Cav-1 is an essential target protein that regulates iron and lipid metabolic homeostasis. It is a pivotal molecule for predicting and protecting against the development of NAFLD. Copyright © 2023 The Author(s).

Original languageEnglish
Article number53
JournalMilitary Medical Research
Volume10
DOIs
Publication statusPublished - Nov 2023

Citation

Deng, G.-H., Wu, C.-F., Li, Y.-J., Shi, H., Zhong, W.-C., Hong, M.-K., Li, J.-J., Zhao, J.-M., Liu, C., Qin, M.-C., Zeng, Z.-Y., Zhang, W.-M., Yung, K. K. L., Lv, Z.-P., & Gao, L. (2023). Caveolin-1 is critical for hepatic iron storage capacity in the development of nonalcoholic fatty liver disease. Military Medical Research, 10, Article 53. https://doi.org/10.1186/s40779-023-00487-3

Keywords

  • Caveolin-1
  • Nonalcoholic fatty liver disease
  • Iron metabolism
  • Ferritin
  • Oxidative stress

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