Egon Demetz1, Piotr Tymoszuk1, Richard Hilbe1, Chiara Volani1, David Haschka1, Christiane Heim1, Kristina Auer1, Daniela Lener2, Lucas B Zeiger1, Christa Pfeifhofer-Obermair1, Anna Boehm1, Gerald J Obermair3,4, Cornelia Ablinger3, Stefan Coassin5, Claudia Lamina5, Juliane Kager1, Verena Petzer1, Malte Asshoff1, Andrea Schroll1, Manfred Nairz1, Stefanie Dichtl1, Markus Seifert1,6, Laura von Raffay1, Christine Fischer1, Marina Barros-Pinkelnig1, Natascha Brigo1, Lara Valente de Souza1,6, Sieghart Sopper7, Jakob Hirsch8, Michael Graber8, Can Gollmann-Tepeköylü8, Johannes Holfeld8, Julia Halper1, Sophie Macheiner9, Johanna Gostner10, Georg F Vogel11, Raimund Pechlaner12, Patrizia Moser13, Medea Imboden14,15, Pedro Marques-Vidal16, Nicole M Probst-Hensch14,15, Heike Meiselbach17, Konstantin Strauch18,19, Annette Peters20,21,22, Bernhard Paulweber23, Johann Willeit12, Stefan Kiechl12, Florian Kronenberg5, Igor Theurl1, Ivan Tancevski1, Guenter Weiss1,6. 1. Department of Internal Medicine II, Medical University of Innsbruck, Anichstraße 35, 6020 Innsbruck, Austria. 2. Department of Internal Medicine III, Medical University of Innsbruck, Anichstraße 35, 6020 Innsbruck, Austria. 3. Department of Physiology and Medical Physics, Medical University of Innsbruck, Fritz-Pregl-Straße 3, 6020 Innsbruck, Austria. 4. Division of Physiology, Karl Landsteiner University of Health Sciences, Dr.-Karl-Dorrek-Straße 30, 3500 Krems, Austria. 5. Department of Genetics and Pharmacology, Institute of Genetic Epidemiology, Medical University of Innsbruck, Schöpfstraße 41, 6020 Innsbruck, Austria. 6. Christian Doppler Laboratory for Iron Metabolism and Anemia Research, Medical University of Innsbruck, Innsbruck, Austria. 7. Department of Internal Medicine V, Medical University of Innsbruck, Anichstraße 35, 6020 Innsbruck, Austria. 8. Department of Cardiac Surgery, Medical University of Innsbruck, Anichstraße 35, 6020 Innsbruck, Austria. 9. Department of Internal Medicine I, Medical University of Innsbruck, Anichstraße 35, 6020 Innsbruck, Austria. 10. Division of Medical Biochemistry, Medical University of Innsbruck, Innrain 80/IV, 6020 Innsbruck, Austria. 11. Department of Pediatrics I, Medical University of Innsbruck, Anichstraße 35, 6020 Innsbruck, Austria. 12. Department of Neurology, Medical University of Innsbruck, Anichstraße 35, 6020 Innsbruck, Austria. 13. Department of Pathology, Innsbruck University Hospital, Anichstraße 35, 6020 Innsbruck, Austria. 14. Swiss Tropical and Public Health Institute, Socinstraße 57, 4051 Basel, Switzerland. 15. Department of Public Health, University of Basel, Bernoullistraße 28, 4056 Basel, Switzerland. 16. Department of Internal Medicine, Lausanne University Hospital, Rue du Bugnon 46, 1011 Lausanne, Switzerland. 17. Department of Nephrology and Hypertension, University Hospital Erlangen, Maximiliansplatz 2, 91054 Erlangen, Germany. 18. Institute of Genetic Epidemiology, Helmholtz Zentrum München-German Research Center for Environmental Health, Ingolstädter Landstraße 1, 85764 Neuherberg, Germany. 19. Institute of Medical Informatics, Biometry and Epidemiology, Ludwig-Maximilians-Universität, Marchioninistraße 15, 81377 Munich, Germany. 20. Institute of Epidemiology II, Helmholtz Zentrum München-German Research Center for Environmental Health, Ingolstädter Landstraße 1, 85764 Neuherberg, Germany. 21. German Center for Diabetes Research, Ingolstädter Landstraße 1, 85764 Neuherberg, Germany. 22. German Center for Cardiovascular Research, Lazarettstraße 36, 80636 Munich, Germany. 23. First Department of Medicine, Paracelsus Medical University Salzburg, Strubergasse 21, 5020 Salzburg, Austria.
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. Published on behalf of the European Society of Cardiology. All rights reserved.
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. Published on behalf of the European Society of Cardiology. All rights reserved.
Authors: Maud Voisin; Elina Shrestha; Claire Rollet; Cyrus A Nikain; Tatjana Josefs; Mélanie Mahé; Tessa J Barrett; Hye Rim Chang; Rachel Ruoff; Jeffrey A Schneider; Michela L Garabedian; Chris Zoumadakis; Chi Yun; Bara Badwan; Emily J Brown; Adam C Mar; Robert J Schneider; Ira J Goldberg; Inés Pineda-Torra; Edward A Fisher; Michael J Garabedian Journal: Commun Biol Date: 2021-03-26