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Demetz, E.* ; Tymoszuk, P.* ; Hilbe, R.* ; Volani, C.* ; Haschka, D.* ; Heim, C.* ; Auer, K.* ; Lener, D.* ; Zeiger, L.B.* ; Pfeifhofer-Obermair, C.* ; Boehm, A.* ; Obermair, G.J.* ; 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, G.F.* ; Pechlaner, R.* ; Moser, P.* ; Imboden, M.* ; Marques-Vidal, P.* ; Probst-Hensch, N.M.* ; Meiselbach, H.* ; Strauch, K. ; Peters, A. ; Paulweber, B.* ; Willeit, J.* ; Kiechl, S.* ; Kronenberg, F.* ; Theurl, I.* ; Tancevski, I.* ; Weiss, G.*

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

Eur. Heart J. 41, 3949–3959 (2020)

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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.

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Publication type Article: Journal article

Document type Scientific Article

Corresponding Author

Keywords Abca1 ; Atherosclerosis ; Haemochromatosis ; Kupffer Cells ; Ldl Receptor; Low-density-lipoprotein; Ester Transfer Protein; Iron Overload; Hereditary Hemochromatosis; Hdl Metabolism; Risk; Inflammation; Macrophages; Efflux; Blood

ISSN (print) / ISBN 0195-668X

e-ISSN 1522-9645

Journal European Heart Journal

Quellenangaben Volume: 41, Issue: 40, Pages: 3949–3959

Publisher Oxford University Press

Publishing Place Great Clarendon St, Oxford Ox2 6dp, England

Non-patent literature Publications

Reviewing status Peer reviewed

Institute(s) Institute of Epidemiology II (EPI2)
Institute of Genetic Epidemiology (IGE)

Grants Swiss National Science Foundation
COMET project VASCage Tyrol of the Austrian Research Promotion Agency FFG
Medical University Innsbruck for young scientists MUI-START
Christian Doppler Society
Doctoral program HOROS
FWF
Austrian Science Fund (FWF)