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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; [...]

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

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  • Medientyp: E-Artikel
  • Titel: The haemochromatosis gene Hfe and Kupffer cells control LDL cholesterol homeostasis and impact on atherosclerosis development
  • Beteiligte: 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; [...]
  • Erschienen: Oxford University Press (OUP), 2020
  • Erschienen in: European Heart Journal
  • Sprache: Englisch
  • DOI: 10.1093/eurheartj/ehaa140
  • ISSN: 0195-668X; 1522-9645
  • Entstehung:
  • Anmerkungen:
  • Beschreibung: <jats:title>Abstract</jats:title> <jats:sec> <jats:title>Aims</jats:title> <jats:p>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.</jats:p> </jats:sec> <jats:sec> <jats:title>Methods and results</jats:title> <jats:p>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.</jats:p> </jats:sec> <jats:sec> <jats:title>Conclusion</jats:title> <jats:p>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.</jats:p> <jats:p /> </jats:sec>
  • Zugangsstatus: Freier Zugang