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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)
Verlagsversion Forschungsdaten DOI PMC
Open Access Green möglich sobald Postprint bei der ZB eingereicht worden ist.
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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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Korrespondenzautor
Schlagwörter 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
Zeitschrift European Heart Journal
Quellenangaben Band: 41, Heft: 40, Seiten: 3949–3959 Artikelnummer: , Supplement: ,
Verlag Oxford University Press
Verlagsort Great Clarendon St, Oxford Ox2 6dp, England
Nichtpatentliteratur Publikationen
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Epidemiology II (EPI2)
Institute of Genetic Epidemiology (IGE)
Förderungen 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)