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

Egon Demetz, Piotr Tymoszuk, Richard Hilbe, Chiara Volani, David Haschka, Christiane Heim, Kristina Auer, Daniela Lener, Lucas B Zeiger, Christa Pfeifhofer-Obermair, Anna Boehm, Gerald J Obermair, Cornelia Ablinger, Stefan Coassin, Claudia Lamina, Juliane Kager, Verena Petzer, Malte Asshoff, Andrea Schroll, Manfred NairzStefanie Dichtl, Markus Seifert, Laura von Raffay, Christine Fischer, Marina Barros-Pinkelnig, Natascha Brigo, Lara Valente de Souza, Sieghart Sopper, Jakob Hirsch, Michael Graber, Can Gollmann-Tepeköylü, Johannes Holfeld, Julia Halper, Sophie Macheiner, Johanna Gostner, Georg F Vogel, Raimund Pechlaner, Patrizia Moser, Medea Imboden, Pedro Marques-Vidal, Nicole M Probst-Hensch, Heike Meiselbach, Konstantin Strauch, Annette Peters, Bernhard Paulweber, Johann Willeit, Stefan Kiechl, Florian Kronenberg, Igor Theurl, Ivan Tancevski, Guenter Weiss

Research output: Journal article (peer-reviewed)Journal article

18 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)3949-3959B
Number of pages11
JournalEuropean Heart Journal
Volume41
Issue number40
DOIs
Publication statusPublished - 21 Oct 2020

Keywords

  • Animals
  • Atherosclerosis/genetics
  • Cholesterol, LDL
  • Clustered Regularly Interspaced Short Palindromic Repeats
  • Genome-Wide Association Study
  • Hemochromatosis/genetics
  • Hemochromatosis Protein
  • Homeostasis
  • Humans
  • Kupffer Cells
  • Mice
  • Receptors, LDL

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