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; Ken Kin Lam Yung; Zhi-Ping Lv; Lei Gao

doi:10.1186/s40779-023-00487-3

Your Location：

Home >

Browse articles >

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

RESEARCH | Updated：2025-12-13

- Caveolin-1 is critical for hepatic iron storage capacity in the development of nonalcoholic fatty liver disease
- Caveolin-1 is critical for hepatic iron storage capacity in the development of nonalcoholic fatty liver disease
- MMR 2024年11卷第2期页码：206-227
- Affiliations：
  
  1.Department of Gastroenterology, Integrated Hospital of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510315, China
  2.School of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510515, China
  3.Department of Hepatology, Cancer Center, Integrated Hospital of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510315, China
  4.Shenzhen Traditional Chinese Medicine Hospital, Shenzhen 518033, Guangdong, China
  5.Department of Biology, Hong Kong Baptist University, Kowloon Tong, Kowloon, Hong Kong SAR 999077, China
- Author bio：
  
  *raygaolei@smu.edu.cn
- Funds：
  
  the National Natural Science Foundation of China(82074131;81774170;82260926);the Guangdong Basic and Applied Basic Research Foundation(2018B030306012;2022A1515220179;2021A1515011667);the Outstanding Youth Development Scheme project of Southern Medical University(G621299870);the Young Elite Scientists Sponsorship Program by CACM(2021-QNRC2-B28);the China Postdoctoral Science Foundation(2022M721532)
- DOI：10.1186/s40779-023-00487-3
  中图分类号：
- 纸质出版：2024-04
- Accepted：
Scan QR Code
Caveolin-1 is critical for hepatic iron storage capacity in the development of nonalcoholic fatty liver disease[J]. MMR, 2024,11(2):206-227.

Cite this article as: Deng GH, Wu CF, Li YJ, Shi H, Zhong WC, Hong MK, et al. Caveolin-1 is critical for hepatic iron storage capacity in the development of nonalcoholic fatty liver disease. Mil Med Res. 2023;10(1):53.
Caveolin-1 is critical for hepatic iron storage capacity in the development of nonalcoholic fatty liver disease[J]. MMR, 2024,11(2):206-227. DOI： 10.1186/s40779-023-00487-3.

Cite this article as: Deng GH, Wu CF, Li YJ, Shi H, Zhong WC, Hong MK, et al. Caveolin-1 is critical for hepatic iron storage capacity in the development of nonalcoholic fatty liver disease. Mil Med Res. 2023;10(1):53. DOI： 10.1186/s40779-023-00487-3.

摘要

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 p

erformed 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 (

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 (

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.

关键词

Keywords

references

Asrani SK , Devarbhavi H , Eaton J , Kamath PS . Burden of liver diseases in the world . J Hepatol . 2019 ; 70 ( 1 ): 151 – 71 .

Moore JB . From sugar to liver fat and public health: systems biology driven studies in understanding non-alcoholic fatty liver disease pathogenesis . Proc Nutr Soc . 2019 ; 78 ( 3 ): 290 – 304 .

Cobbina E , Akhlaghi F . Non-alcoholic fatty liver disease (NAFLD)—pathogenesis, classification, and effect on drug metabolizing enzymes and transporters . Drug Metab Rev . 2017 ; 49 ( 2 ): 197 – 211 .

Diehl AM , Day C . Cause, pathogenesis, and treatment of nonalcoholic steatohepatitis . New Engl J Med . 2017 ; 377 ( 21 ): 2063 – 72 .

Sanyal AJ , Friedman SL , McCullough AJ , Dimick-Santos L , et al . Challenges and opportunities in drug and biomarker development for nonalcoholic steatohepatitis: findings and recommendations from an American Association for the Study of Liver Diseases-US Food and Drug Administration Joint Workshop . Hepatology . 2015 ; 61 ( 4 ): 1392 – 405 .

Corradini E , Buzzetti E , Dongiovanni P , Scarlini S , Caleffi A , Pelusi S , et al . Ceruloplasmin gene variants are associated with hyperferritinemia and increased liver iron in patients with NAFLD . J Hepatol . 2021 ; 75 ( 3 ): 506 – 13 .

Gao H , Jin Z , Bandyopadhyay G , Wang G , Zhang D , Rocha KCE , et al . Aberrant iron distribution via hepatocyte-stellate cell axis drives liver lipogenesis and fibrosis . Cell Metab . 2022 ; 34 ( 8 ): 1201-13.e5 .

Heslin AM , O'Donnell A , Buffini M , Nugent AP , Walton J , Flynn A , et al . Risk of iron overload in obesity and implications in metabolic health . Nutrients . 2021 ; 13 ( 5 ): 1539 .

Guo QL , Dai XL , Yin MY , Cheng HW , Qian HS , Wang H , et al . Nanosensitizers for sonodynamic therapy for glioblastoma multiforme: current progress and future perspectives . Mil Med Res . 2022 ; 9 ( 1 ): 26 .

Takahashi M , Mizumura K , Gon Y , Shimizu T , Kozu Y , Shikano S , et al . Iron-dependent mitochondrial dysfunction contributes to the pathogenesis of pulmonary fibrosis . Front Pharmacol . 2022 ; 12 : 643980 .

Ortega MA , Fraile-Martinez O , García-Montero C , Haro S , Álvarez-Mon MÁ , De Leon-Oliva D , et al . A comprehensive look at the psychoneuroimmunoendocrinology of spinal cord injury and its progression: mechanisms and clinical opportunities . Mil Med Res . 2023 ; 10 ( 1 ): 26 .

Yeo JH , Colonne CK , Tasneem N , Cosgriff MP , Fraser ST . The iron islands: erythroblastic islands and iron metabolism . Biochim Biophys Acta Gen Subj . 2019 ; 1863 ( 2 ): 466 – 71 .

Dev S , Babitt JL . Overview of iron metabolism in health and disease . Hemodial Int . 2017 ; 21 ( Suppl 1 ): S6 – 20 .

Nairz M , Theurl I , Swirski FK , Weiss G . “Pumping iron”-how macrophages handle iron at the systemic, microenvironmental, and cellular levels . Pflug Arch Eur J Phy . 2017 ; 469 ( 3–4 ): 397 – 418 .

Imran M , Chalmel F , Sergent O , Evrard B , Le Mentec H , Legrand A , et al . Transcriptomic analysis in zebrafish larvae identifies iron-dependent mitochondrial dysfunction as a possible key event of NAFLD progression induced by benzo[a]pyrene/ethanol co-exposure . Cell Biol Toxicol . 2023 ; 39 ( 2 ): 371 – 90 .

Bosch M , Marí M , Herms A , Fernández A , Fajardo A , Kassan A , et al . Caveolin-1 deficiency causes cholesterol-dependent mitochondrial dysfunction and apoptotic susceptibility . Curr Biol . 2011 ; 21 ( 8 ): 681 – 6 .

Fernández-Rojo MA , Gongora M , Fitzsimmons RL , Martel N , Martin SD , Nixon SJ , et al . Caveolin-1 is necessary for hepatic oxidative lipid metabolism: evidence for crosstalk between caveolin-1 and bile acid signaling . Cell Rep . 2013 ; 4 ( 2 ): 238 – 47 .

Takeda M , Sakaguchi T , Hiraide T , Shibasaki Y , Morita Y , Kikuchi H , et al . Role of caveolin-1 in hepatocellular carcinoma arising from non-alcoholic fatty liver disease . Cancer Sci . 2018 ; 109 ( 8 ): 2401 – 11 .

Deng G , Li Y , Ma S , Gao Z , Zeng T , Chen L , et al . Caveolin-1 dictates ferroptosis in the execution of acute immune-mediated hepatic damage by attenuating nitrogen stress . Free Radic Biol Med . 2020 ; 148 : 151 – 61 .

Wang K , Li C , Lin X , Sun H , Xu R , Li Q , et al . Targeting alkaline ceramidase 3 alleviates the severity of nonalcoholic steato-hepatitis by reducing oxidative stress . Cell Death Dis . 2020 ; 11 ( 1 ): 28 .

Yang Y , Chen J , Gao Q , Shan X , Wang J , Lv Z . Study on the attenuated effect of ginkgolide B on ferroptosis in high fat diet induced nonalcoholic fatty liver disease . Toxicology . 2020 ; 445 : 152599 .

Wang J , Ma J , Nie H , Zhang X , Zhang P , She ZG , et al . Hepatic regulator of G protein signaling 5 ameliorates nonalcoholic fatty liver disease by suppressing transforming growth factor beta-activated kinase 1-c-Jun N-terminal kinase/p38 signaling . Hepatology . 2021 ; 73 ( 1 ): 104 – 25 .

Gao L , Zhou Y , Zhong W , Zhao X , Chen C , Chen X , et al . Caveolin-1 is essential for protecting against binge drinking-induced liver damage through inhibiting reactive nitrogen species . Hepatology . 2014 ; 60 ( 2 ): 687 – 99 .

Mo C , Xie S , Liu B , Zhong W , Zeng T , Huang S , et al . Indoleamine 2,3-dioxygenase 1 limits hepatic inflammatory cells recruitment and promotes bile duct ligation-induced liver fibrosis . Cell Death Dis . 2021 ; 12 ( 1 ): 16 .

Abaj F , Mirzaei K . Caveolin-1 genetic polymorphism interacts with PUFA to modulate metabolic syndrome risk . Brit J Nutr . 2022 ; 127 ( 9 ): 1281 – 8 .

Aali Y , Shiraseb F , Abaj F , Koohdani F , Mirzaei K . The interactions between dietary fats intake and Caveolin 1 rs 3807992 poly-morphism with fat distribution in overweight and obese women: a cross-sectional study . BMC Med Genomics . 2021 ; 14 ( 1 ): 265 .

Preziosi ME , Singh S , Valore EV , Jung G , Popovic B , Poddar M , et al . Mice lacking liver-specific beta-catenin develop steatohepatitis and fibrosis after iron overload . J Hepatol . 2017 ; 67 ( 2 ): 360 – 9 .

Wu A , Feng B , Yu J , Yan L , Che L , Zhuo Y , et al . Fibroblast growth factor 21 attenuates iron overload-induced liver injury and fibrosis by inhibiting ferroptosis . Redox Biol . 2021 ; 46 : 102131 .

Ganz T . Macrophages and iron metabolism . Microbiol Spectr . 2016 . https://doi.org/10.1128/microbiolspec.MCHD-0037-2016.

Frietze KK , Brown AM , Das D , Franks RG , Cunningham JL , Hayward M , et al . Lipotoxicity reduces DDX58/Rig-1 expression and activity leading to impaired autophagy and cell death . Autophagy . 2022 ; 18 ( 1 ): 142 – 60 .

Sohail AM , Khawar MB , Afzal A , Hassan A , Shahzaman S , Ali A . Multifaceted roles of extracellular RNAs in different diseases . Mil Med Res . 2022 ; 9 ( 1 ): 43 .

Neuman MG , French SW , Zakhari S , Malnick S , Seitz HK , Cohen LB , et al . Alcohol, microbiome, life style influence alcohol and non-alcoholic organ damage . Exp Mol Pathol . 2017 ; 102 ( 1 ): 162 – 80 .

Tilg H , Moschen AR . Evolution of inflammation in nonalcoholic fatty liver disease: the multiple parallel hits hypothesis . Hepatology . 2010 ; 52 ( 5 ): 1836 – 46 .

Videla LA , Valenzuela R . Perspectives in liver redox imbalance: toxicological and pharmacological aspects underlying iron overloading, nonalcoholic fatty liver disease, and thyroid hormone action . BioFactors . 2022 ; 48 ( 2 ): 400 – 15 .

Fernandez-Rojo MA , Ramm GA . Caveolin-1 function in liver physiology and disease . Trends Mol Med . 2016 ; 22 ( 10 ): 889 – 904 .

Han M , Nwosu ZC , Pioronska W , Ebert MP , Dooley S , Meyer C . Caveolin-1 impacts on TGF-beta regulation of metabolic gene signatures in hepatocytes . Front Physiol . 2020 ; 10 : 1606 .

Xue W , Wang J , Jiang W , Shi C , Wang X , Huang Y , et al . Caveolin-1 alleviates lipid accumulation in NAFLD associated with promoting autophagy by inhibiting the Akt/mTOR pathway . Eur J Pharmacol . 2020 ; 871 : 172910 .

Zhang X , Ramirez CM , Aryal B , Madrigal-Matute J , Liu X , Diaz A , et al . Cav-1 (caveolin-1) deficiency increases autophagy in the endothelium and attenuates vascular inflammation and atherosclerosis . Arterioscl Throm Vas . 2020 ; 40 ( 6 ): 1510 – 22 .

Zeng H , Qin H , Liao M , Zheng E , Luo X , Xiao A , et al . CD36 promotes de novo lipogenesis in hepatocytes through INSIG2-dependent SREBP1 processing . Mol Metab . 2022 ; 57 : 101428 .

Han M , Pioronska W , Wang S , Nwosu ZC , Sticht C , Wang S , et al . Hepatocyte caveolin-1 modulates metabolic gene profiles and functions in non-alcoholic fatty liver disease . Cell Death Dis . 2020 ; 11 ( 2 ): 104 .

Li Y , Xiu W , Yang K , Wen Q , Yuwen L , Luo Z , et al . A multifunctional Fenton nanoagent for microenvironment-selective anti-biofilm and anti-inflammatory therapy . Mater Horiz . 2021 ; 8 ( 4 ): 1264 – 71 .

Konstorum A , Lynch ML , Torti SV , Torti FM , Laubenbacher RC . A systems biology approach to understanding the pathophysiology of high-grade serous ovarian cancer: focus on iron and fatty acid metabolism . OMICS . 2018 ; 22 ( 7 ): 502 – 13 .

McNally JR , Mehlenbacher MR , Luscieti S , Smith GL , Reutovich AA , Maura P , et al . Mutant L-chain ferritins that cause neuroferritinopathy alter ferritin functionality and iron permeability . Metallomics . 2019 ; 11 ( 10 ): 1635 – 47 .

Zarjou A , Jeney V , Arosio P , Poli M , Antal-Szalmás P , Agarwal A , et al . Ferritin prevents calcification and osteoblastic differentiation of vascular smooth muscle cells . J Am Soc Nephrol . 2009 ; 20 ( 6 ): 1254 – 63 .

Kensler TW , Wakabayash N , Biswal S . Cell survival responses to environmental stresses via the Keap1-Nrf2-ARE pathway . Annu Rev Pharmacol . 2007 ; 47 : 89 – 116 .

Loboda A , Damulewicz M , Pyza E , Jozkowicz A , Dulak J . Role of Nrf2/HO-1 system in development, oxidative stress response and diseases: an evolutionarily conserved mechanism . Cell Mol Life Sci . 2016 ; 73 ( 17 ): 3221 – 47 .

Kim SY , Jeong JM , Kim SJ , Seo W , Kim MH , Choi WM , et al . Pro-inflammatory hepatic macrophages generate ROS through NADPH oxidase 2 via endocytosis of monomeric TLR4-MD2 complex . Nat Commun . 2017 ; 8 ( 1 ): 2247 .

Nakashima H , Nakashima M , Kinoshita M , Ikarashi M , Miyazaki H , Hanaka H , et al . Activation and increase of radio-sensitive CD11b + recruited Kupffer cells/macrophages in diet-induced steatohepatitis in FGF5 deficient mice . Sci Rep . 2016 ; 6 : 34466 .

Thomas AJ , Ogilvy CS , Griessenauer CJ , Hanafy KA . Macrophage CD163 expression in cerebrospinal fluid: association with subarachnoid hemorrhage outcome . J Neurosurg . 2019 ; 131 ( 1 ): 47 – 53 .

Bloomer SA . Hepatic macrophage abundance and phenotype in aging and liver iron accumulation . Int J Mol Sci . 2022 ; 23 ( 12 ): 6502 .

Kovtunovych G , Eckhaus MA , Ghosh MC , Ollivierre-Wilson H , Rouault TA . Dysfunction of the heme recycling system in heme oxygenase 1-deficient mice: effects on macrophage viability and tissue iron distribution . Blood . 2010 ; 116 ( 26 ): 6054 – 62 .

McGaha TL , Chen Y , Ravishankar B , van Rooijen N , Karlsson MCI . Marginal zone macrophages suppress innate and adaptive immunity to apoptotic cells in the spleen . Blood . 2011 ; 117 ( 20 ): 5403 – 12 .

Campbell NK , Fitzgerald HK , Dunne A . Regulation of inflammation by the antioxidant haem oxygenase 1 . Nat Rev Immunol . 2021 ; 21 ( 7 ): 411 – 25 .

Ma S , Dubin AE , Zhang YX , Mousavi SAR , Wang Y , Coombs AM , et al . A role of PIEZO1 in iron metabolism in mice and humans . Cell . 2021 ; 184 ( 4 ): 969-82.e13 .

Mayneris-Perxachs J , Cardellini M , Hoyles L , Latorre J , Davato F , Moreno-Navarrete JM , et al . Iron status influences non-alcoholic fatty liver disease in obesity through the gut microbiome . Microbiome . 2021 ; 9 ( 1 ): 104 .

浏览量

Downloads

CSCD

文章被引用时，请邮件提醒。

Submit

工具集

关联资源

Cardiovascular adaptations and pathological changes induced by spaceflight: from cellular mechanisms to organ-level impacts

Advances in the mechanism of small nucleolar RNA and its role in DNA damage response

FDA-approved cannabidiol [Epidiolex^®] alleviates Gulf War Illness-linked cognitive and mood dysfunction, hyperalgesia, neuroinflammatory signaling, and declined neurogenesis

Minimal active domain of human salivary histatin 1 is efficacious in promoting acute skin wound healing

Lower blood malondialdehyde is associated with past pesticide exposure: findings in Gulf War illness and healthy controls