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

Détails

ID Serval
serval:BIB_1EB7027A6A1A
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Institution
Titre
The haemochromatosis gene Hfe and Kupffer cells control LDL cholesterol homeostasis and impact on atherosclerosis development.
Périodique
European heart journal
Auteur⸱e⸱s
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.
ISSN
1522-9645 (Electronic)
ISSN-L
0195-668X
Statut éditorial
Publié
Date de publication
21/10/2020
Peer-reviewed
Oui
Volume
41
Numéro
40
Pages
3949-3959
Langue
anglais
Notes
Publication types: Journal Article
Publication Status: ppublish
Résumé
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.
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.
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.
Mots-clé
ABCA1, Atherosclerosis, Haemochromatosis, Kupffer cells, LDL receptor
Pubmed
Web of science
Création de la notice
01/04/2020 17:24
Dernière modification de la notice
14/01/2021 6:22
Données d'usage