The haemochromatosis gene Hfe and Kupffer cells control LDL cholesterol homeostasis and impact on atherosclerosis development. (30th March 2020)

• Record Type: Journal Article
• Authors: Demetz, Egon; Tymoszuk, Piotr; Hilbe, Richard; Volani, Chiara; Haschka, David; Heim, Christiane; Auer, Kristina; Lener, Daniela; Zeiger, Lucas B; Pfeifhofer-Obermair, Christa; Boehm, Anna; Obermair, Gerald J; Ablinger, Cornelia; Coassin, Stefan; Lamina, Claudia; Kager, Juliane; Petzer, Verena; Asshoff, Malte; Schroll, Andrea; Nairz, Manfred; Dichtl, Stefanie; Seifert, Markus; von Raffay, Laura; Fischer, Christine; Barros-Pinkelnig, Marina; Brigo, Natascha; Valente de Souza, Lara; Sopper, Sieghart; Hirsch, Jakob; Graber, Michael; Gollmann-Tepeköylü, Can; Holfeld, Johannes; Halper, Julia; Macheiner, Sophie; Gostner, Johanna; Vogel, Georg F; Pechlaner, Raimund; Moser, Patrizia; Imboden, Medea; Marques-Vidal, Pedro; Probst-Hensch, Nicole M; Meiselbach, Heike; Strauch, Konstantin; Peters, Annette; Paulweber, Bernhard; Willeit, Johann; Kiechl, Stefan; Kronenberg, Florian; Theurl, Igor; Tancevski, Ivan; Weiss, Guenter;
• Is Part Of: European heart journal. Volume 41:Number 40(2020)
• Page Start: 3949
• Page End: 3959
• Publication Date: 2020-03-30
• Subjects: Haemochromatosis -- Atherosclerosis -- LDL receptor -- Kupffer cells -- ABCA1; Cardiology -- Periodicals; Heart -- Diseases -- Periodicals; 616.12005
• DOI: 10.1093/eurheartj/ehaa140
• Languages: English
• ISSNs: 0195-668X

Abstract

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.