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