The haemochromatosis gene Hfe and Kupffer cells control LDL cholesterol homeostasis and impact on atherosclerosis development
Demetz E, Tymoszuk P, Hilbe R, Volani C, Haschka D, Heim C, Auer K, Lener D, Zeiger LB, Pfeifhofer-Obermair C, Boehm A, Obermair GJ, Ablinger C, Coassin S, Lamina C, Kager J, Petzer V, Asshoff M, Schroll A, Nairz M, Dichtl S, Seifert M, von Raffay L, Fischer C, Barros-Pinkelnig M, Brigo N, Valente de Souza L, Sopper S, Hirsch J, Graber M, Gollmann-Tepeköylü C, Holfeld J, Halper J, Macheiner S, Gostner J, Vogel GF, Pechlaner R, Moser P, Imboden M, Marques-Vidal P, Probst-Hensch NM, Meiselbach H, Strauch K, Peters A, Paulweber B, Willeit J, Kiechl S, Kronenberg F, Theurl I, Tancevski I, Weiss G (2020)
Publication Type: Journal article
Publication year: 2020
Journal
Book Volume: 41
Pages Range: 3949-3959
Journal Issue: 40
DOI: 10.1093/eurheartj/ehaa140
Abstract
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.
Involved external institutions
Medizinische Universität Innsbruck
Austria (AT)
Tirol Kliniken GmbH
Austria (AT)
Schweizerisches Tropen- und Public Health-Institut (Swiss TPH)
Switzerland (CH)
Lausanne University Hospital / Centre hospitalier universitaire vaudois (CHUV)
Switzerland (CH)
Helmholtz Zentrum München - Deutsches Forschungszentrum für Gesundheit und Umwelt (HMGU) / Helmholtz Munich
Germany (DE)
Paracelsus Medizinische Privatuniversität
Austria (AT)
Austria (AT)
Tirol Kliniken GmbH
Austria (AT)
Schweizerisches Tropen- und Public Health-Institut (Swiss TPH)
Switzerland (CH)
Lausanne University Hospital / Centre hospitalier universitaire vaudois (CHUV)
Switzerland (CH)
Helmholtz Zentrum München - Deutsches Forschungszentrum für Gesundheit und Umwelt (HMGU) / Helmholtz Munich
Germany (DE)
Paracelsus Medizinische Privatuniversität
Austria (AT)
How to cite
APA:
Demetz, E., Tymoszuk, P., Hilbe, R., Volani, C., Haschka, D., Heim, C.,... Weiss, G. (2020). The haemochromatosis gene Hfe and Kupffer cells control LDL cholesterol homeostasis and impact on atherosclerosis development. European Heart Journal, 41(40), 3949-3959. https://doi.org/10.1093/eurheartj/ehaa140
MLA:
Demetz, Egon, et al. "The haemochromatosis gene Hfe and Kupffer cells control LDL cholesterol homeostasis and impact on atherosclerosis development." European Heart Journal 41.40 (2020): 3949-3959.
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