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 Tybjærg-Hansen, Jan Albert Kuivenhoven

Journal: Arteriosclerosis, thrombosis, and vascular biology 2019;38(7):1440-1453

PMID: 29853565

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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 (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 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 : 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 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.

Address: From the Department of Pediatrics, Section of Molecular Genetics, University Medical Centre Groningen, University of Groningen, The Netherlands (F.O., J.C.W., B.v.d.S., J.A.K.).; Department of Vascular Medicine (J.C.v.C., G.M.D.-T., K.G.H.).; Department of Clinical Biochemistry, Rigshospitalet (N.D., R.F.-S., A.T.-H.).; Department of Biochemistry and Molecular Cell Biology, University Medical Center Hamburg-Eppendorf, Germany (J.H.).; Department of Genetics, University Medical Centre Groningen, The Netherlands (R.J.S.).; Department of Pathology and Laboratory Medicine, Metabolic Diseases Institute, University of Cincinnati College of Medicine, OH (D.Y.H.).; Department Experimental Vascular Medicine (G.M.D.-T.), Academic Medical Center, Amsterdam, The Netherlands.; Copenhagen City Heart Study, Frederiksberg Hospital (A.T.-H.), Copenhagen University Hospital and Faculty of Health and Medical Sciences, University of Copenhagen, Denmark.; From the Department of Pediatrics, Section of Molecular Genetics, University Medical Centre Groningen, University of Groningen, The Netherlands (F.O., J.C.W., B.v.d.S., J.A.K.) [email protected].

DOI: 10.1161/ATVBAHA.117.310309