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 Nairz; Stefanie 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

doi:10.1093/eurheartj/ehaa140

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

Division of Physiology

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

34 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 language	English
Pages (from-to)	3949-3959B
Number of pages	11
Journal	European Heart Journal
Volume	41
Issue number	40
DOIs	https://doi.org/10.1093/eurheartj/ehaa140
Publication status	Published - 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

Access to Document

10.1093/eurheartj/ehaa140

Cite this

Demetz, E., Tymoszuk, P., Hilbe, R., Volani, C., Haschka, D., Heim, C., Auer, K., Lener, D., Zeiger, L. B., Pfeifhofer-Obermair, C., Boehm, A., Obermair, G. J., Ablinger, C., Coassin, S., Lamina, C., Kager, J., Petzer, V., Asshoff, M., Schroll, A., ... Weiss, G. (2020). The haemochromatosis gene Hfe and Kupffer cells control LDL cholesterol homeostasis and impact on atherosclerosis development. European Heart Journal, 41(40), 3949-3959B. https://doi.org/10.1093/eurheartj/ehaa140

@article{9a4627098a7c464c8012f662084dd5ab,

title = "The haemochromatosis gene Hfe and Kupffer cells control LDL cholesterol homeostasis and impact on atherosclerosis development",

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 = "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",

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

year = "2020",

month = oct,

day = "21",

doi = "10.1093/eurheartj/ehaa140",

language = "English",

volume = "41",

pages = "3949--3959B",

journal = "European Heart Journal",

issn = "0195-668X",

publisher = "Oxford University Press",

number = "40",

}

Demetz, E, Tymoszuk, P, Hilbe, R, Volani, C, Haschka, D, Heim, C, Auer, K, Lener, D, Zeiger, LB, Pfeifhofer-Obermair, C, Boehm, A, Obermair, GJ, Ablinger, C, Coassin, S, Lamina, C, Kager, J, Petzer, V, Asshoff, M, Schroll, A, Nairz, M, Dichtl, S, Seifert, M, von Raffay, L, Fischer, C, Barros-Pinkelnig, M, Brigo, N, Valente de Souza, L, Sopper, S, Hirsch, J, Graber, M, Gollmann-Tepeköylü, C, Holfeld, J, Halper, J, Macheiner, S, Gostner, J, Vogel, GF, Pechlaner, R, Moser, P, Imboden, M, Marques-Vidal, P, Probst-Hensch, NM, Meiselbach, H, Strauch, K, Peters, A, Paulweber, B, Willeit, J, Kiechl, S, Kronenberg, F, Theurl, I, Tancevski, I & Weiss, G 2020, 'The haemochromatosis gene Hfe and Kupffer cells control LDL cholesterol homeostasis and impact on atherosclerosis development', European Heart Journal, vol. 41, no. 40, pp. 3949-3959B. https://doi.org/10.1093/eurheartj/ehaa140

TY - JOUR

T1 - The haemochromatosis gene Hfe and Kupffer cells control LDL cholesterol homeostasis and impact on atherosclerosis development

AU - Demetz, Egon

AU - Tymoszuk, Piotr

AU - Hilbe, Richard

AU - Volani, Chiara

AU - Haschka, David

AU - Heim, Christiane

AU - Auer, Kristina

AU - Lener, Daniela

AU - Zeiger, Lucas B

AU - Pfeifhofer-Obermair, Christa

AU - Boehm, Anna

AU - Obermair, Gerald J

AU - Ablinger, Cornelia

AU - Coassin, Stefan

AU - Lamina, Claudia

AU - Kager, Juliane

AU - Petzer, Verena

AU - Asshoff, Malte

AU - Schroll, Andrea

AU - Nairz, Manfred

AU - Dichtl, Stefanie

AU - Seifert, Markus

AU - von Raffay, Laura

AU - Fischer, Christine

AU - Barros-Pinkelnig, Marina

AU - Brigo, Natascha

AU - Valente de Souza, Lara

AU - Sopper, Sieghart

AU - Hirsch, Jakob

AU - Graber, Michael

AU - Gollmann-Tepeköylü, Can

AU - Holfeld, Johannes

AU - Halper, Julia

AU - Macheiner, Sophie

AU - Gostner, Johanna

AU - Vogel, Georg F

AU - Pechlaner, Raimund

AU - Moser, Patrizia

AU - Imboden, Medea

AU - Marques-Vidal, Pedro

AU - Probst-Hensch, Nicole M

AU - Meiselbach, Heike

AU - Strauch, Konstantin

AU - Peters, Annette

AU - Paulweber, Bernhard

AU - Willeit, Johann

AU - Kiechl, Stefan

AU - Kronenberg, Florian

AU - Theurl, Igor

AU - Tancevski, Ivan

AU - Weiss, Guenter

PY - 2020/10/21

Y1 - 2020/10/21

N2 - 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.

AB - 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.

KW - Animals

KW - Atherosclerosis/genetics

KW - Cholesterol, LDL

KW - Clustered Regularly Interspaced Short Palindromic Repeats

KW - Genome-Wide Association Study

KW - Hemochromatosis/genetics

KW - Hemochromatosis Protein

KW - Homeostasis

KW - Humans

KW - Kupffer Cells

KW - Mice

KW - Receptors, LDL

UR - http://www.scopus.com/inward/record.url?scp=85090485035&partnerID=8YFLogxK

U2 - 10.1093/eurheartj/ehaa140

DO - 10.1093/eurheartj/ehaa140

M3 - Journal article

C2 - 32227235

SN - 0195-668X

VL - 41

SP - 3949-3959B

JO - European Heart Journal

JF - European Heart Journal

IS - 40

ER -

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

Abstract

Keywords

Access to Document

Other files and links

Fingerprint

Cite this