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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)

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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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