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
Federico OldoniJan Albert Kuivenhoven

Abstract

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. 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. This study provides the first evidence that rare variants in L...Continue Reading

References

May 9, 1995·Proceedings of the National Academy of Sciences of the United States of America·T E WillnowJ Herz
Oct 3, 1999·The EMBO Journal·M HeinrichS Schütze
Sep 11, 2004·Arteriosclerosis, Thrombosis, and Vascular Biology·Wilfried Le GoffJonathan D Smith
Oct 8, 2004·Molecular Biology of the Cell·Salim Maa BaredGerd Schmitz
Jul 28, 2005·Cancer Letters·Emmanuelle Liaudet-CoopmanFrançoise Vignon
Nov 1, 2005·European Journal of Immunology·Catherine X MossColin Watts
Oct 13, 2006·The Journal of Biological Chemistry·Bassam HaidarYves L Marcel
Mar 12, 2009·Biochemical and Biophysical Research Communications·Yu-Chun LinVivian C Yang
Jun 27, 2009·Circulation Research·Roshni R SingarajaMichael R Hayden
Jul 6, 2010·Nucleic Acids Research·Kai WangHakon Hakonarson
Sep 28, 2010·Biological Chemistry·Marco DieckmannJoachim Herz
May 21, 2013·Arteriosclerosis, Thrombosis, and Vascular Biology·Mohammad Mahdi MotazackerG Kees Hovingh
Oct 8, 2013·Nature Genetics·Cristen J WillerUNKNOWN Global Lipids Genetics Consortium
Oct 26, 2013·Nature Protocols·F Ann RanFeng Zhang
Feb 18, 2017·Journal of the American College of Cardiology·Thomas R WebbUNKNOWN Myocardial Infarction Genetics and CARDIoGRAM Exome Consortia Investigators

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Citations

Dec 24, 2019·Arteriosclerosis, Thrombosis, and Vascular Biology·Hong S LuAlan Daugherty
Feb 9, 2020·Cardiovascular Drugs and Therapy·Xiandong MengYonggang Guo

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Methods Mentioned

BETA
Protein Assay
transfection
transfections
scraping
Exome Sequencing
protein folding
confocal microscopy

Software Mentioned

SDS
Image Laboratory
GraphPad
ANNOVAR
ZEN
SE
Stata
Skyline
Origene

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