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

被引：35

作者：

Demetz, Egon ^{[1
]}

Tymoszuk, Piotr ^{[1
]}

Hilbe, Richard ^{[1
]}

Volani, Chiara ^{[1
]}

Haschka, David ^{[1
]}

Heim, Christiane ^{[1
]}

Auer, Kristina ^{[1
]}

Lener, Daniela ^{[2
]}

Zeiger, Lucas B. ^{[1
]}

Pfeifhofer-Obermair, Christa ^{[1
]}

Boehm, Anna ^{[1
]}

Obermair, Gerald J. ^{[3
,4
]}

Ablinger, Cornelia ^{[3
]}

Coassin, Stefan ^{[5
]}

Lamina, Claudia ^{[5
]}

Kager, Juliane ^{[1
]}

Petzer, Verena ^{[1
]}

Asshoff, Malte ^{[1
]}

Schroll, Andrea ^{[1
]}

Nairz, Manfred ^{[1
]}

Dichtl, Stefanie ^{[1
]}

Seifert, Markus ^{[1
,6
]}

von Raffay, Laura ^{[1
]}

Fischer, Christine ^{[1
]}

Barros-Pinkelnig, Marina ^{[1
]}

Brigo, Natascha ^{[1
]}

de Souza, Lara Valente ^{[1
,6
]}

Sopper, Sieghart ^{[7
]}

Hirsch, Jakob ^{[8
]}

Graber, Michael ^{[8
]}

Gollmann-Tepekoeylue, Can ^{[8
]}

Holfeld, Johannes ^{[8
]}

Halper, Julia ^{[1
]}

Macheiner, Sophie ^{[9
]}

Gostner, Johanna ^{[10
]}

Vogel, Georg F. ^{[11
]}

Pechlaner, Raimund ^{[12
]}

Moser, Patrizia ^{[13
]}

Imboden, Medea ^{[14
,15
]}

Marques-Vidal, Pedro ^{[16
]}

Probst-Hensch, Nicole M. ^{[14
,15
]}

Meiselbach, Heike ^{[17
]}

Strauch, Konstantin ^{[18
,19
]}

Peters, Annette ^{[20
,21
,22
]}

Paulweber, Bernhard ^{[23
]}

Willeit, Johann ^{[12
]}

Kiechl, Stefan ^{[12
]}

Kronenberg, Florian ^{[5
]}

Theurl, Igor ^{[1
]}

Tancevski, Ivan ^{[1
]}

机构：

[1] Med Univ Innsbruck, Dept Internal Med 2, Anichstr 35, A-6020 Innsbruck, Austria

[2] Med Univ Innsbruck, Dept Internal Med 3, Anichstr 35, A-6020 Innsbruck, Austria

[3] Med Univ Innsbruck, Dept Physiol & Med Phys, Fritz Pregl Str 3, A-6020 Innsbruck, Austria

[4] Karl Landsteiner Univ Hlth Sci, Div Physiol, Dr Karl Dorrek Str 30, A-3500 Krems, Austria

[5] Med Univ Innsbruck, Inst Genet Epidemiol, Dept Genet & Pharmacol, Schopfstr 41, A-6020 Innsbruck, Austria

[6] Med Univ Innsbruck, Christian Doppler Lab Iron Metab & Anemia Res, Innsbruck, Austria

[7] Med Univ Innsbruck, Dept Internal Med 5, Anichstr 35, A-6020 Innsbruck, Austria

[8] Med Univ Innsbruck, Dept Cardiac Surg, Anichstr 35, A-6020 Innsbruck, Austria

[9] Med Univ Innsbruck, Dept Internal Med &, Anichstr 35, A-6020 Innsbruck, Austria

[10] Med Univ Innsbruck, Div Med Biochem, Innrain 80-4, A-6020 Innsbruck, Austria

[11] Med Univ Innsbruck, Dept Pediat 1, Anichstr 35, A-6020 Innsbruck, Austria

[12] Med Univ Innsbruck, Dept Neurol, Anichstr 35, A-6020 Innsbruck, Austria

[13] Univ Innsbruck Hosp, Dept Pathol, Anichstr 35, A-6020 Innsbruck, Austria

[14] Swiss Trop & Publ Hlth Inst, Socinstr 57, CH-4051 Basel, Switzerland

[15] Univ Basel, Dept Publ Hlth, Bernoullistr 28, CH-4056 Basel, Switzerland

[16] Lausanne Univ Hosp, Dept Internal Med, Rue Bugnon 46, CH-1011 Lausanne, Switzerland

[17] Univ Hosp Erlangen, Dept Nephrol & Hypertens, Maximilianspl 2, D-91054 Erlangen, Germany

[18] Helmholtz Zentrum Munchen, Inst Genet Epidemiol, German Res Ctr Environm, Landstr 1, D-85764 Neuherberg, Germany

[19] Ludwig Maximilians Univ Munchen, Inst Med Informat Biometry & Epidemiol, Marchioninistr 15, D-81377 Munich, Germany

[20] Helmholtz Zentrum Munchen, Inst Epidemiol 2, German Res Ctr Environm Hlth, Ingolstadter Landstr 1, D-85764 Neuherberg, Germany

[21] German Ctr Diabet Res, Ingolstadter Landstr 1, D-85764 Neuherberg, Germany

[22] German Ctr Cardiovasc Res, Lazarettstr 36, D-80636 Munich, Germany

[23] Paracelsus Med Univ Salzburg, Dept Med 1, Strubergasse 21, A-5020 Salzburg, Austria

来源：

EUROPEAN HEART JOURNAL | 2020年 / 41卷 / 40期

基金：

瑞士国家科学基金会; 奥地利科学基金会;

关键词：

Haemochromatosis; Atherosclerosis; LDL receptor; Kupffer cells; ABCA1; LOW-DENSITY-LIPOPROTEIN; ESTER TRANSFER PROTEIN; IRON OVERLOAD; HEREDITARY HEMOCHROMATOSIS; HDL METABOLISM; RISK; INFLAMMATION; MACROPHAGES; EFFLUX; BLOOD;

D O I：

10.1093/eurheartj/ehaa140

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

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.

引用

页码：3949 / +

页数：13

共 37 条

[31] Iron overload in hypercholesterolemic rats affects iron homeostasis and serum lipids but not blood pressure
Turbino-Ribeiro, SML
Silva, ME
Chianca, DA
de Paula, H
Cardoso, LM
Colombari, E
Pedrosa, ML
[J]. JOURNAL OF NUTRITION, 2003, 133 (01) : 15 - 20
[32] Important role for bone marrow-derived cholesteryl ester transfer protein in lipoprotein cholesterol redistribution and atherosclerotic lesion development in LDL receptor knockout mice
Van Eck, Miranda
Ye, Dan
Hildebrand, Reeni B.
Kruijt, J. Kar
de Haan, Willeke
Hoekstra, Menno
Rensen, Patrick C. N.
Ehnholm, Christian
Jauhiainen, Matti
Van Berkel, Theo J. C.
[J]. CIRCULATION RESEARCH, 2007, 100 (05) : 678 - 685
[33] Atherosclerosis is aggravated by iron overload and ameliorated by dietary and pharmacological iron restriction
Vinchi, Francesca
Porto, Graca
Simmelbauer, Andreas
Altamura, Sandro
Passos, Sara T.
Garbowski, Maciej
Silva, Andre M. N.
Spaich, Sebastian
Seide, Svenja E.
Sparla, Richard
Hentze, Matthias W.
Muckenthaler, Martina U.
[J]. EUROPEAN HEART JOURNAL, 2020, 41 (28) : 2681 - +
[34] Plasma Cholesteryl Ester Transfer Protein Is Predominantly Derived From Kupffer Cells
Wang, Yanan
van der Tuin, Sam
Tjeerdema, Nathanja
van Dam, Andrea D.
Rensen, Sander S.
Hendrikx, Tim
Berbee, Jimmy F. P.
Atanasovska, Biljana
Fu, Jingyuan
Hoekstra, Menno
Bekkering, Siroon
Riksen, Niels P.
Buurman, Wim A.
Greve, Jan Willem
Hofker, Marten H.
Shiri-Sverdlov, Ronit
Meijer, Onno C.
Smit, Johannes W. A.
Havekes, Louis M.
van Dijk, Ko Willems
Rensen, Patrick C. N.
[J]. HEPATOLOGY, 2015, 62 (06) : 1710 - 1722
[35] Genetic mechanisms and modifying factors in hereditary hemochromatosis
Weiss, Guenter
[J]. NATURE REVIEWS GASTROENTEROLOGY & HEPATOLOGY, 2010, 7 (01) : 50 - 58
[36] Discovery and refinement of loci associated with lipid levels
Willer, Cristen J.
Schmidt, Ellen M.
Sengupta, Sebanti
Peloso, Gina M.
Gustafsson, Stefan
Kanoni, Stavroula
Ganna, Andrea
Chen, Jin
Buchkovich, Martin L.
Mora, Samia
Beckmann, Jacques S.
Bragg-Gresham, Jennifer L.
Chang, Hsing-Yi
Demirkan, Ayse
Den Hertog, Heleen M.
Do, Ron
Donnelly, Louise A.
Ehret, Georg B.
Esko, Tonu
Feitosa, Mary F.
Ferreira, Teresa
Fischer, Krista
Fontanillas, Pierre
Fraser, Ross M.
Freitag, Daniel F.
Gurdasani, Deepti
Heikkila, Kauko
Hyppoenen, Elina
Isaacs, Aaron
Jackson, Anne U.
Johansson, Asa
Johnson, Toby
Kaakinen, Marika
Kettunen, Johannes
Kleber, Marcus E.
Li, Xiaohui
Luan, Jian'an
Lyytikainen, Leo-Pekka
Magnusson, Patrik K. E.
Mangino, Massimo
Mihailov, Evelin
Montasser, May E.
Mueller-Nurasyid, Martina
Nolte, Ilja M.
O'Connell, Jeffrey R.
Palmer, Cameron D.
Perola, Markus
Petersen, Ann-Kristin
Sanna, Serena
Saxena, Richa
[J]. NATURE GENETICS, 2013, 45 (11) : 1274 - +
[37] ATP-Binding Cassette Transporters A1 and G1, HDL Metabolism, Cholesterol Efflux, and Inflammation: Important Targets for the Treatment of Atherosclerosis
Ye, Dan
Lammers, Bart
Zhao, Ying
Meurs, Illiana
Van Berkel, Theo J. C.
Van Eck, Miranda
[J]. CURRENT DRUG TARGETS, 2011, 12 (05) : 647 - 660

← 1 2 3 4 →