The haemochromatosis gene Hfe and Kupffer cells control LDL cholesterol homeostasis and impact on atherosclerosis development
| Autor: | Chiara Volani, Claudia Lamina, Juliane Kager, Marina Barros-Pinkelnig, Markus Seifert, J. Hirsch, Verena Petzer, Gerald J. Obermair, Heike Meiselbach, Piotr Tymoszuk, Stefan Coassin, Malte Asshoff, David Haschka, Lucas B Zeiger, Konstantin Strauch, Stefanie Dichtl, Sieghart Sopper, Laura von Raffay, Manfred Nairz, Florian Kronenberg, Patrizia Moser, Georg F. Vogel, Natascha Brigo, Egon Demetz, Nicole Probst-Hensch, Lara Valente de Souza, Christiane Heim, Richard Hilbe, Pedro Marques-Vidal, Daniela Lener, Stefan Kiechl, Julia Halper, Guenter Weiss, S Macheiner, Christine Fischer, Johann Willeit, Annette Peters, M. Graber, Can Gollmann-Tepeköylü, Medea Imboden, Bernhard Paulweber, Johanna M. Gostner, Johannes Holfeld, Ivan Tancevski, Raimund Pechlaner, Kristina Auer, Christa Pfeifhofer-Obermair, Andrea Schroll, Anna Boehm, Igor Theurl, Cornelia Ablinger |
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| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
Apolipoprotein E
medicine.medical_specialty Kupffer Cells Single-nucleotide polymorphism 030204 cardiovascular system & hematology Abca1 Atherosclerosis Haemochromatosis Ldl Receptor 03 medical and health sciences chemistry.chemical_compound Mice 0302 clinical medicine Internal medicine medicine ABCA1 Gene Animals Homeostasis Humans Clustered Regularly Interspaced Short Palindromic Repeats Hemochromatosis Protein Hemochromatosis 030304 developmental biology 0303 health sciences biology Cholesterol business.industry Cholesterol LDL medicine.disease Endocrinology chemistry Receptors LDL ABCA1 LDL receptor biology.protein lipids (amino acids peptides and proteins) Cardiology and Cardiovascular Medicine business Genome-Wide Association Study |
| Zdroj: | Eur. Heart J. 41, 3949–3959 (2020) |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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