Naturally Occurring Variants in LRP1 (Low-Density Lipoprotein Receptor-Related Protein 1) Affect HDL (High-Density Lipoprotein) Metabolism Through ABCA1 (ATP-Binding Cassette A1) and SR-B1 (Scavenger Receptor Class B Type 1) in Humans

Federico Oldoni; Julian C. van Capelleveen; Nawar Dalila; Justina C. Wolters; Joerg Heeren; Richard J. Sinke; David Y. Hui; Geesje M. Dallinga-Thie; Ruth Frikke-Schmidt; Kees G. Hovingh; Bart van de Sluis; Anne Tybjaerg-Hansen; Jan Albert Kuivenhoven

doi:10.1161/ATVBAHA.117.310309

Naturally Occurring Variants in LRP1 (Low-Density Lipoprotein Receptor-Related Protein 1) Affect HDL (High-Density Lipoprotein) Metabolism Through ABCA1 (ATP-Binding Cassette A1) and SR-B1 (Scavenger Receptor Class B Type 1) in Humans

Federico Oldoni, Julian C. van Capelleveen, Nawar Dalila, Justina C. Wolters, Joerg Heeren, Richard J. Sinke, David Y. Hui, Geesje M. Dallinga-Thie, Ruth Frikke-Schmidt, Kees G. Hovingh, Bart van de Sluis, Anne Tybjaerg-Hansen, Jan Albert Kuivenhoven^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

13 Citations (Scopus)

Abstract

Objective Studies into the role of LRP1 (low-density lipoprotein receptor-related protein 1) in human lipid metabolism are scarce. Although it is known that a common variant in LRP1 (rs116133520) is significantly associated with HDL-C (high-density lipoprotein cholesterol), the mechanism underlying this observation is unclear. In this study, we set out to study the functional effects of 2 rare LRP1 variants identified in subjects with extremely low HDL-C levels.

Approach and Results In 2 subjects with HDL-C below the first percentile for age and sex and moderately elevated triglycerides, we identified 2 rare variants in LRP1: p.Val3244Ile and p.Glu3983Asp. Both variants decrease LRP1 expression and stability. We show in a series of translational experiments that these variants culminate in reduced trafficking of ABCA1 (ATP-binding cassette A1) to the cell membrane. This is accompanied by an increase in cell surface expression of SR-B1 (scavenger receptor class B type 1). Combined these effects may contribute to low HDL-C levels in our study subjects. Supporting these findings, we provide epidemiological evidence that rs116133520 is associated with apo (apolipoprotein) A1 but not with apoB levels.

Conclusions This study provides the first evidence that rare variants in LRP1 are associated with changes in human lipid metabolism. Specifically, this study shows that LRP1 may affect HDL metabolism by virtue of its effect on both ABCA1 and SR-B1.

Visual Overview-An online visual overview is available for this article.

Original language	English
Pages (from-to)	1440-1453
Number of pages	14
Journal	Arteriosclerosis, thrombosis, and vascular biology
Volume	38
Issue number	7
DOIs	https://doi.org/10.1161/ATVBAHA.117.310309
Publication status	Published - Jul-2018

Keywords

apolipoprotein
cell membrane
HDL cholesterol
lipid metabolism
low-density lipoprotein receptor-related protein 1
triglycerides
ABCA1-MEDIATED LIPID EFFLUX
CATHEPSIN-D
CHYLOMICRON REMNANTS
CHOLESTEROL EFFLUX
TANGIER-DISEASE
TRANSPORTER A1
CELLS
GENE
PROTEASE
TRAFFICKING

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Naturally Occurring Variants in LRP1 (Low-Density Lipoprotein Receptor–Related Protein 1) Affect HDL (High-Density Lipoprotein) Metabolism Through ABCA1 (ATP-Binding Cassette A1) and SR-B1 (Scavenger Receptor Class B Type 1) in Humans
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Oldoni, F., van Capelleveen, J. C., Dalila, N., Wolters, J. C., Heeren, J., Sinke, R. J., Hui, D. Y., Dallinga-Thie, G. M., Frikke-Schmidt, R., Hovingh, K. G., van de Sluis, B., Tybjaerg-Hansen, A., & Kuivenhoven, J. A. (2018). Naturally Occurring Variants in LRP1 (Low-Density Lipoprotein Receptor-Related Protein 1) Affect HDL (High-Density Lipoprotein) Metabolism Through ABCA1 (ATP-Binding Cassette A1) and SR-B1 (Scavenger Receptor Class B Type 1) in Humans. Arteriosclerosis, thrombosis, and vascular biology, 38(7), 1440-1453. https://doi.org/10.1161/ATVBAHA.117.310309

Oldoni, Federico ; van Capelleveen, Julian C. ; Dalila, Nawar et al. / Naturally Occurring Variants in LRP1 (Low-Density Lipoprotein Receptor-Related Protein 1) Affect HDL (High-Density Lipoprotein) Metabolism Through ABCA1 (ATP-Binding Cassette A1) and SR-B1 (Scavenger Receptor Class B Type 1) in Humans. In: Arteriosclerosis, thrombosis, and vascular biology. 2018 ; Vol. 38, No. 7. pp. 1440-1453.

@article{237cf8a83fd54a19ba3bf438e2075161,

title = "Naturally Occurring Variants in LRP1 (Low-Density Lipoprotein Receptor-Related Protein 1) Affect HDL (High-Density Lipoprotein) Metabolism Through ABCA1 (ATP-Binding Cassette A1) and SR-B1 (Scavenger Receptor Class B Type 1) in Humans",

abstract = "Objective Studies into the role of LRP1 (low-density lipoprotein receptor-related protein 1) in human lipid metabolism are scarce. Although it is known that a common variant in LRP1 (rs116133520) is significantly associated with HDL-C (high-density lipoprotein cholesterol), the mechanism underlying this observation is unclear. In this study, we set out to study the functional effects of 2 rare LRP1 variants identified in subjects with extremely low HDL-C levels.Approach and Results In 2 subjects with HDL-C below the first percentile for age and sex and moderately elevated triglycerides, we identified 2 rare variants in LRP1: p.Val3244Ile and p.Glu3983Asp. Both variants decrease LRP1 expression and stability. We show in a series of translational experiments that these variants culminate in reduced trafficking of ABCA1 (ATP-binding cassette A1) to the cell membrane. This is accompanied by an increase in cell surface expression of SR-B1 (scavenger receptor class B type 1). Combined these effects may contribute to low HDL-C levels in our study subjects. Supporting these findings, we provide epidemiological evidence that rs116133520 is associated with apo (apolipoprotein) A1 but not with apoB levels.Conclusions This study provides the first evidence that rare variants in LRP1 are associated with changes in human lipid metabolism. Specifically, this study shows that LRP1 may affect HDL metabolism by virtue of its effect on both ABCA1 and SR-B1.Visual Overview-An online visual overview is available for this article.",

keywords = "apolipoprotein, cell membrane, HDL cholesterol, lipid metabolism, low-density lipoprotein receptor-related protein 1, triglycerides, ABCA1-MEDIATED LIPID EFFLUX, CATHEPSIN-D, CHYLOMICRON REMNANTS, CHOLESTEROL EFFLUX, TANGIER-DISEASE, TRANSPORTER A1, CELLS, GENE, PROTEASE, TRAFFICKING",

author = "Federico Oldoni and {van Capelleveen}, {Julian C.} and Nawar Dalila and Wolters, {Justina C.} and Joerg Heeren and Sinke, {Richard J.} and Hui, {David Y.} and Dallinga-Thie, {Geesje M.} and Ruth Frikke-Schmidt and Hovingh, {Kees G.} and {van de Sluis}, Bart and Anne Tybjaerg-Hansen and Kuivenhoven, {Jan Albert}",

note = "{\textcopyright} 2018 American Heart Association, Inc.",

year = "2018",

month = jul,

doi = "10.1161/ATVBAHA.117.310309",

language = "English",

volume = "38",

pages = "1440--1453",

journal = "Arteriosclerosis, thrombosis, and vascular biology",

issn = "1079-5642",

publisher = "LIPPINCOTT WILLIAMS & WILKINS",

number = "7",

}

Oldoni, F, van Capelleveen, JC, Dalila, N, Wolters, JC, Heeren, J, Sinke, RJ, Hui, DY, Dallinga-Thie, GM, Frikke-Schmidt, R, Hovingh, KG, van de Sluis, B, Tybjaerg-Hansen, A & Kuivenhoven, JA 2018, 'Naturally Occurring Variants in LRP1 (Low-Density Lipoprotein Receptor-Related Protein 1) Affect HDL (High-Density Lipoprotein) Metabolism Through ABCA1 (ATP-Binding Cassette A1) and SR-B1 (Scavenger Receptor Class B Type 1) in Humans', Arteriosclerosis, thrombosis, and vascular biology, vol. 38, no. 7, pp. 1440-1453. https://doi.org/10.1161/ATVBAHA.117.310309

Naturally Occurring Variants in LRP1 (Low-Density Lipoprotein Receptor-Related Protein 1) Affect HDL (High-Density Lipoprotein) Metabolism Through ABCA1 (ATP-Binding Cassette A1) and SR-B1 (Scavenger Receptor Class B Type 1) in Humans. / Oldoni, Federico; van Capelleveen, Julian C.; Dalila, Nawar et al.
In: Arteriosclerosis, thrombosis, and vascular biology, Vol. 38, No. 7, 07.2018, p. 1440-1453.

Research output: Contribution to journal › Article › Academic › peer-review

TY - JOUR

T1 - Naturally Occurring Variants in LRP1 (Low-Density Lipoprotein Receptor-Related Protein 1) Affect HDL (High-Density Lipoprotein) Metabolism Through ABCA1 (ATP-Binding Cassette A1) and SR-B1 (Scavenger Receptor Class B Type 1) in Humans

AU - Oldoni, Federico

AU - van Capelleveen, Julian C.

AU - Dalila, Nawar

AU - Wolters, Justina C.

AU - Heeren, Joerg

AU - Sinke, Richard J.

AU - Hui, David Y.

AU - Dallinga-Thie, Geesje M.

AU - Frikke-Schmidt, Ruth

AU - Hovingh, Kees G.

AU - van de Sluis, Bart

AU - Tybjaerg-Hansen, Anne

AU - Kuivenhoven, Jan Albert

PY - 2018/7

Y1 - 2018/7

N2 - Objective Studies into the role of LRP1 (low-density lipoprotein receptor-related protein 1) in human lipid metabolism are scarce. Although it is known that a common variant in LRP1 (rs116133520) is significantly associated with HDL-C (high-density lipoprotein cholesterol), the mechanism underlying this observation is unclear. In this study, we set out to study the functional effects of 2 rare LRP1 variants identified in subjects with extremely low HDL-C levels.Approach and Results In 2 subjects with HDL-C below the first percentile for age and sex and moderately elevated triglycerides, we identified 2 rare variants in LRP1: p.Val3244Ile and p.Glu3983Asp. Both variants decrease LRP1 expression and stability. We show in a series of translational experiments that these variants culminate in reduced trafficking of ABCA1 (ATP-binding cassette A1) to the cell membrane. This is accompanied by an increase in cell surface expression of SR-B1 (scavenger receptor class B type 1). Combined these effects may contribute to low HDL-C levels in our study subjects. Supporting these findings, we provide epidemiological evidence that rs116133520 is associated with apo (apolipoprotein) A1 but not with apoB levels.Conclusions This study provides the first evidence that rare variants in LRP1 are associated with changes in human lipid metabolism. Specifically, this study shows that LRP1 may affect HDL metabolism by virtue of its effect on both ABCA1 and SR-B1.Visual Overview-An online visual overview is available for this article.

AB - Objective Studies into the role of LRP1 (low-density lipoprotein receptor-related protein 1) in human lipid metabolism are scarce. Although it is known that a common variant in LRP1 (rs116133520) is significantly associated with HDL-C (high-density lipoprotein cholesterol), the mechanism underlying this observation is unclear. In this study, we set out to study the functional effects of 2 rare LRP1 variants identified in subjects with extremely low HDL-C levels.Approach and Results In 2 subjects with HDL-C below the first percentile for age and sex and moderately elevated triglycerides, we identified 2 rare variants in LRP1: p.Val3244Ile and p.Glu3983Asp. Both variants decrease LRP1 expression and stability. We show in a series of translational experiments that these variants culminate in reduced trafficking of ABCA1 (ATP-binding cassette A1) to the cell membrane. This is accompanied by an increase in cell surface expression of SR-B1 (scavenger receptor class B type 1). Combined these effects may contribute to low HDL-C levels in our study subjects. Supporting these findings, we provide epidemiological evidence that rs116133520 is associated with apo (apolipoprotein) A1 but not with apoB levels.Conclusions This study provides the first evidence that rare variants in LRP1 are associated with changes in human lipid metabolism. Specifically, this study shows that LRP1 may affect HDL metabolism by virtue of its effect on both ABCA1 and SR-B1.Visual Overview-An online visual overview is available for this article.

KW - apolipoprotein

KW - cell membrane

KW - HDL cholesterol

KW - lipid metabolism

KW - low-density lipoprotein receptor-related protein 1

KW - triglycerides

KW - ABCA1-MEDIATED LIPID EFFLUX

KW - CATHEPSIN-D

KW - CHYLOMICRON REMNANTS

KW - CHOLESTEROL EFFLUX

KW - TANGIER-DISEASE

KW - TRANSPORTER A1

KW - CELLS

KW - GENE

KW - PROTEASE

KW - TRAFFICKING

U2 - 10.1161/ATVBAHA.117.310309

DO - 10.1161/ATVBAHA.117.310309

M3 - Article

C2 - 29853565

SN - 1079-5642

VL - 38

SP - 1440

EP - 1453

JO - Arteriosclerosis, thrombosis, and vascular biology

JF - Arteriosclerosis, thrombosis, and vascular biology

IS - 7

ER -

Oldoni F, van Capelleveen JC, Dalila N, Wolters JC, Heeren J, Sinke RJ et al. Naturally Occurring Variants in LRP1 (Low-Density Lipoprotein Receptor-Related Protein 1) Affect HDL (High-Density Lipoprotein) Metabolism Through ABCA1 (ATP-Binding Cassette A1) and SR-B1 (Scavenger Receptor Class B Type 1) in Humans. Arteriosclerosis, thrombosis, and vascular biology. 2018 Jul;38(7):1440-1453. doi: 10.1161/ATVBAHA.117.310309