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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

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., Jul-2018, In : Arteriosclerosis, thrombosis, and vascular biology. 38, 7, p. 1440-1453 14 p.

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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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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.

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Original languageEnglish
Pages (from-to)1440-1453
Number of pages14
JournalArteriosclerosis, thrombosis, and vascular biology
Volume38
Issue number7
Publication statusPublished - 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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