The haemochromatosis gene Hfe and Kupffer cells control LDL cholesterol homeostasis and impact on atherosclerosis development-Reference-Cited by-同舟云学术

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

Published:2020-03-30 Issue:40 Volume:41 Page:3949-3959
ISSN:0195-668X
Container-title:European Heart Journal
language:en
Short-container-title:

Author:

Demetz Egon¹,Tymoszuk Piotr¹^ORCID,Hilbe Richard¹,Volani Chiara¹^ORCID,Haschka David¹^ORCID,Heim Christiane¹,Auer Kristina¹,Lener Daniela²^ORCID,Zeiger Lucas B¹^ORCID,Pfeifhofer-Obermair Christa¹^ORCID,Boehm Anna¹^ORCID,Obermair Gerald J³⁴^ORCID,Ablinger Cornelia³^ORCID,Coassin Stefan⁵^ORCID,Lamina Claudia⁵,Kager Juliane¹,Petzer Verena¹^ORCID,Asshoff Malte¹,Schroll Andrea¹^ORCID,Nairz Manfred¹^ORCID,Dichtl Stefanie¹^ORCID,Seifert Markus¹⁶,von Raffay Laura¹,Fischer Christine¹,Barros-Pinkelnig Marina¹,Brigo Natascha¹^ORCID,Valente de Souza Lara¹⁶^ORCID,Sopper Sieghart⁷^ORCID,Hirsch Jakob⁸^ORCID,Graber Michael⁸^ORCID,Gollmann-Tepeköylü Can⁸^ORCID,Holfeld Johannes⁸^ORCID,Halper Julia¹^ORCID,Macheiner Sophie⁹^ORCID,Gostner Johanna¹⁰^ORCID,Vogel Georg F¹¹,Pechlaner Raimund¹²^ORCID,Moser Patrizia¹³,Imboden Medea¹⁴¹⁵^ORCID,Marques-Vidal Pedro¹⁶^ORCID,Probst-Hensch Nicole M¹⁴¹⁵,Meiselbach Heike¹⁷,Strauch Konstantin¹⁸¹⁹,Peters Annette²⁰²¹²²,Paulweber Bernhard²³^ORCID,Willeit Johann¹²^ORCID,Kiechl Stefan¹²^ORCID,Kronenberg Florian⁵^ORCID,Theurl Igor¹^ORCID,Tancevski Ivan¹^ORCID,Weiss Guenter¹⁶^ORCID

Affiliation:

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

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.

Funder

Austrian Science Fund

Doctoral program HOROS

Christian Doppler Society

Medical University Innsbruck for young scientists MUI-START

COMET project VASCage Tyrol [K-Project

Austrian Research Promotion Agency FFG

Swiss National Science Foundation

Publisher

Oxford University Press (OUP)

Subject

Cardiology and Cardiovascular Medicine