The haemochromatosis gene Hfe and Kupffer cells control LDL cholesterol homeostasis and impact on atherosclerosis development

Demetz, E. and Tymoszuk, P. and Hilbe, R. and Volani, C. and Haschka, D. and Heim, C. and Auer, K. and Lener, D. and Zeiger, L. B. and Pfeifhofer-Obermair, C. and Boehm, A. and Obermair, G. J. and Ablinger, C. and Coassin, S. and Lamina, C. and Kager, J. and Petzer, V. and Asshoff, M. and Schroll, A. and Nairz, M. and Dichtl, S. and Seifert, M. and von Raffay, L. and Fischer, C. and Barros-Pinkelnig, M. and Brigo, N. and Valente de Souza, L. and Sopper, S. and Hirsch, J. and Graber, M. and Gollmann-Tepekoylu, C. and Holfeld, J. and Halper, J. and Macheiner, S. and Gostner, J. and Vogel, G. F. and Pechlaner, R. and Moser, P. and Imboden, M. and Marques-Vidal, P. and Probst-Hensch, N. M. and Meiselbach, H. and Strauch, K. and Peters, A. and Paulweber, B. and Willeit, J. and Kiechl, S. and Kronenberg, F. and Theurl, I. and Tancevski, I. and Weiss, G.. (2020) The haemochromatosis gene Hfe and Kupffer cells control LDL cholesterol homeostasis and impact on atherosclerosis development. European heart journal, 41 (40). pp. 3949-3959.

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Official URL: https://edoc.unibas.ch/91054/

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AIMS: Imbalances of iron metabolism have been linked to the development of atherosclerosis. However, subjects with hereditary haemochromatosis have a lower prevalence of cardiovascular disease. The aim of our study was to understand the underlying mechanisms by combining data from genome-wide association study analyses in humans, CRISPR/Cas9 genome editing, and loss-of-function studies in mice. METHODS AND RESULTS: Our analysis of the Global Lipids Genetics Consortium (GLGC) dataset revealed that single nucleotide polymorphisms (SNPs) in the haemochromatosis gene HFE associate with reduced low-density lipoprotein cholesterol (LDL-C) in human plasma. The LDL-C lowering effect could be phenocopied in dyslipidaemic ApoE-/- mice lacking Hfe, which translated into reduced atherosclerosis burden. Mechanistically, we identified HFE as a negative regulator of LDL receptor expression in hepatocytes. Moreover, we uncovered liver-resident Kupffer cells (KCs) as central players in cholesterol homeostasis as they were found to acquire and transfer LDL-derived cholesterol to hepatocytes in an Abca1-dependent fashion, which is controlled by iron availability. CONCLUSION: Our results disentangle novel regulatory interactions between iron metabolism, KC biology and cholesterol homeostasis which are promising targets for treating dyslipidaemia but also provide a mechanistic explanation for reduced cardiovascular morbidity in subjects with haemochromatosis.
Faculties and Departments:09 Associated Institutions > Swiss Tropical and Public Health Institute (Swiss TPH)
09 Associated Institutions > Swiss Tropical and Public Health Institute (Swiss TPH) > Department of Epidemiology and Public Health (EPH) > Chronic Disease Epidemiology > Exposome Science (Probst-Hensch)
03 Faculty of Medicine > Departement Public Health > Sozial- und Präventivmedizin > Exposome Science (Probst-Hensch)
UniBasel Contributors:Probst-Hensch, Nicole and Imboden, Medea
Item Type:Article, refereed
Article Subtype:Research Article
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:27 Dec 2022 16:20
Deposited On:27 Dec 2022 16:20

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