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

Eur Heart J. 2020 Oct 21;41(40):3949-3959. doi: 10.1093/eurheartj/ehaa140.

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.

Keywords: ABCA1; Atherosclerosis; Haemochromatosis; Kupffer cells; LDL receptor.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

  • Cholesterol, LDL
  • HFE protein, human
  • Hemochromatosis Protein
  • Hfe protein, mouse
  • Receptors, LDL