TY - JOUR
T1 - The haemochromatosis gene Hfe and Kupffer cells control LDL cholesterol homeostasis and impact on atherosclerosis development
AU - Demetz, Egon
AU - Tymoszuk, Piotr
AU - Hilbe, Richard
AU - Volani, Chiara
AU - Haschka, David
AU - Heim, Christiane
AU - Auer, Kristina
AU - Lener, Daniela
AU - Zeiger, Lucas B
AU - Pfeifhofer-Obermair, Christa
AU - Boehm, Anna
AU - Obermair, Gerald J
AU - Ablinger, Cornelia
AU - Coassin, Stefan
AU - Lamina, Claudia
AU - Kager, Juliane
AU - Petzer, Verena
AU - Asshoff, Malte
AU - Schroll, Andrea
AU - Nairz, Manfred
AU - Dichtl, Stefanie
AU - Seifert, Markus
AU - von Raffay, Laura
AU - Fischer, Christine
AU - Barros-Pinkelnig, Marina
AU - Brigo, Natascha
AU - Valente de Souza, Lara
AU - Sopper, Sieghart
AU - Hirsch, Jakob
AU - Graber, Michael
AU - Gollmann-Tepeköylü, Can
AU - Holfeld, Johannes
AU - Halper, Julia
AU - Macheiner, Sophie
AU - Gostner, Johanna
AU - Vogel, Georg F
AU - Pechlaner, Raimund
AU - Moser, Patrizia
AU - Imboden, Medea
AU - Marques-Vidal, Pedro
AU - Probst-Hensch, Nicole M
AU - Meiselbach, Heike
AU - Strauch, Konstantin
AU - Peters, Annette
AU - Paulweber, Bernhard
AU - Willeit, Johann
AU - Kiechl, Stefan
AU - Kronenberg, Florian
AU - Theurl, Igor
AU - Tancevski, Ivan
AU - Weiss, Guenter
N1 - Funding Information:
This work was supported by the Austrian Science Fund (FWF), FWF project [TRP-188] (to G.W.), Doctoral program HOROS [W-1253] (to G.W. C.V., V.P., S.D., F.K., and M.B.-P.), the Christian Doppler Society (to G.W.), and by the intramural funding programme of the Medical University Innsbruck for young scientists MUI-START, Project [2017-01-011] (to E.D.). S.K., J.W., G.W., and I.T. are supported by COMET project VASCage Tyrol [K-Project No. 843536] of the Austrian Research Promotion Agency FFG. SAPALDIA was funded by the Swiss National Science Foundation [33CS30-148470/1&2] (to N.M.P.-H.).
Publisher Copyright:
© 2020 Published on behalf of the European Society of Cardiology. All rights reserved.
PY - 2020/10/21
Y1 - 2020/10/21
N2 - 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.
AB - 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.
KW - Animals
KW - Atherosclerosis/genetics
KW - Cholesterol, LDL
KW - Clustered Regularly Interspaced Short Palindromic Repeats
KW - Genome-Wide Association Study
KW - Hemochromatosis/genetics
KW - Hemochromatosis Protein
KW - Homeostasis
KW - Humans
KW - Kupffer Cells
KW - Mice
KW - Receptors, LDL
UR - http://www.scopus.com/inward/record.url?scp=85090485035&partnerID=8YFLogxK
U2 - 10.1093/eurheartj/ehaa140
DO - 10.1093/eurheartj/ehaa140
M3 - Journal article
C2 - 32227235
SN - 0195-668X
VL - 41
SP - 3949-3959B
JO - European Heart Journal
JF - European Heart Journal
IS - 40
ER -