A Synonymous Variant in Scavenger Receptor, Class B, Type I Gene is Associated with Lower SR-BI Protein Expression and Function

Overview

Journal Atherosclerosis

Publisher Elsevier

Specialty Cardiology & Vascular Diseases

Date 2010 Jan 12

PMID 20060115

Citations 24

Authors

Jason Constantineau

Erin Greason

Michael West

Megan Filbin

Jeffrey S Kieft

Martha Z Carletti

Lane K Christenson

Annabelle Rodriguez

Affiliations

Soon will be listed here.

Abstract

Objective: A synonymous variant within scavenger receptor class B type I gene (SCARB1), exon 8 rs5888, has been associated with altered lipid levels and cardiovascular risk in humans. The objective was to determine if rs5888 decreased SR-BI protein expression and function in vitro.

Methods: SR-BI RNA secondary structure, turnover, polysomal distribution and protein expression were examined in COS cells transfected with wild-type or rs5888-SR-BI plasmids by selective 2'-hydroxyl acylation and primer extension assays, actinomycin D inhibition, polysomal profiling, and western blotting. SR-BI function in murine macrophages stably expressing wild-type or rs5888-SR-BI was assessed by measuring the specific cell association of (125)I,(3)H-cholesteryl ester (CE) radiolabeled HDL.

Results: Rs5888 changed RNA secondary structure and led to marked differences in the polysomal profiles compared with wild-type transcript (p<0.02). As compared to wild-type cells, COS cells expressing rs5888 had significantly lower SR-BI protein expression (p<0.04), but no difference in total RNA transcript levels. There were no differences in SR-BI RNA turnover in murine macrophages, whereas specific cell association of (125)I (p<0.0001) or (3)H-CE (p<0.00001) was significantly lower in rs5888 cells.

Conclusions: The rs5888 variant affected SR-BI RNA secondary structure, protein translation, and was significantly associated with reduced SR-BI protein expression and function in vitro.

Citing Articles

Scavenger receptor class B type I genetic variants associated with disease severity in chronic hepatitis C virus infection.

Arandhara V, McClure C, Tarr A, Chappell S, Morgan K, Baumert T J Med Virol. 2022; 95(1):e28331.

PMID: 36415047 PMC: 10100136. DOI: 10.1002/jmv.28331.

HDL and Scavenger Receptor Class B Type I (SRBI).

Yu H Adv Exp Med Biol. 2022; 1377:79-93.

PMID: 35575922 DOI: 10.1007/978-981-19-1592-5_6.

Expression Levels and Genetic Polymorphism of Scavenger Receptor Class B Type 1 as a Biomarker of Type 2 Diabetes Mellitus.

Wamique M, Himanshu D, Ali W Sultan Qaboos Univ Med J. 2022; 22(1):117-122.

PMID: 35299814 PMC: 8904105. DOI: 10.18295/squmj.4.2021.042.

Functional Deletion/Insertion Promoter Variants in Associated With Increased Susceptibility to Lipid Profile Abnormalities and Coronary Heart Disease.

Hu S, Hu D, Wei H, Li S, Wang D, Li C Front Cardiovasc Med. 2022; 8:800873.

PMID: 35097019 PMC: 8793335. DOI: 10.3389/fcvm.2021.800873.

Apolipoprotein A1-Related Proteins and Reverse Cholesterol Transport in Antiatherosclerosis Therapy: Recent Progress and Future Perspectives.

Xu X, Song Z, Mao B, Xu G Cardiovasc Ther. 2022; 2022:4610834.

PMID: 35087605 PMC: 8763555. DOI: 10.1155/2022/4610834.

References

Rigotti A, Edelman E, Seifert P, Iqbal S, DeMattos R, Temel R . Regulation by adrenocorticotropic hormone of the in vivo expression of scavenger receptor class B type I (SR-BI), a high density lipoprotein receptor, in steroidogenic cells of the murine adrenal gland. J Biol Chem. 1996; 271(52):33545-9. DOI: 10.1074/jbc.271.52.33545. View

Komar A . Genetics. SNPs, silent but not invisible. Science. 2006; 315(5811):466-7. DOI: 10.1126/science.1138239. View

Kimchi-Sarfaty C, Oh J, Kim I, Sauna Z, Calcagno A, Ambudkar S . A "silent" polymorphism in the MDR1 gene changes substrate specificity. Science. 2006; 315(5811):525-8. DOI: 10.1126/science.1135308. View

Sauna Z, Kimchi-Sarfaty C, Ambudkar S, Gottesman M . Silent polymorphisms speak: how they affect pharmacogenomics and the treatment of cancer. Cancer Res. 2007; 67(20):9609-12. DOI: 10.1158/0008-5472.CAN-07-2377. View

Kraemer F, Shen W, Harada K, Patel S, Osuga J, Ishibashi S . Hormone-sensitive lipase is required for high-density lipoprotein cholesteryl ester-supported adrenal steroidogenesis. Mol Endocrinol. 2003; 18(3):549-57. DOI: 10.1210/me.2003-0179. View

SCHRIEWER H, Jabs H, Schultze J, Assmann G . Preparation of high-density lipoproteins labelled exclusively at the cholesteryl ester moiety. Clin Chim Acta. 1982; 123(1-2):139-44. DOI: 10.1016/0009-8981(82)90122-x. View

Signori E, Bagni C, Papa S, Primerano B, Rinaldi M, Amaldi F . A somatic mutation in the 5'UTR of BRCA1 gene in sporadic breast cancer causes down-modulation of translation efficiency. Oncogene. 2001; 20(33):4596-600. DOI: 10.1038/sj.onc.1204620. View

Acton S, Rigotti A, Landschulz K, Xu S, Hobbs H, Krieger M . Identification of scavenger receptor SR-BI as a high density lipoprotein receptor. Science. 1996; 271(5248):518-20. DOI: 10.1126/science.271.5248.518. View

West M, Greason E, Kolmakova A, Jahangiri A, Asztalos B, Pollin T . Scavenger receptor class B type I protein as an independent predictor of high-density lipoprotein cholesterol levels in subjects with hyperalphalipoproteinemia. J Clin Endocrinol Metab. 2009; 94(4):1451-7. PMC: 2682469. DOI: 10.1210/jc.2008-1223. View

10.

Nielsen K, Sorensen S, Cartegni L, Corydon T, Doktor T, Schroeder L . Seemingly neutral polymorphic variants may confer immunity to splicing-inactivating mutations: a synonymous SNP in exon 5 of MCAD protects from deleterious mutations in a flanking exonic splicing enhancer. Am J Hum Genet. 2007; 80(3):416-32. PMC: 1821120. DOI: 10.1086/511992. View

11.

Langer C, Gansz B, Goepfert C, Engel T, Uehara Y, von Dehn G . Testosterone up-regulates scavenger receptor BI and stimulates cholesterol efflux from macrophages. Biochem Biophys Res Commun. 2002; 296(5):1051-7. DOI: 10.1016/s0006-291x(02)02038-7. View

12.

Azhar S, Nomoto A, REAVEN E . Simultaneous induction of an HDL receptor protein (SR-BI) and the selective uptake of HDL-cholesteryl esters in a physiologically relevant steroidogenic cell model. J Lipid Res. 1998; 39(8):1616-28. View

13.

Cao G, Zhao L, Stangl H, Hasegawa T, Richardson J, Parker K . Developmental and hormonal regulation of murine scavenger receptor, class B, type 1. Mol Endocrinol. 1999; 13(9):1460-73. DOI: 10.1210/mend.13.9.0346. View

14.

Chinetti G, Gbaguidi F, Griglio S, Mallat Z, Antonucci M, Poulain P . CLA-1/SR-BI is expressed in atherosclerotic lesion macrophages and regulated by activators of peroxisome proliferator-activated receptors. Circulation. 2000; 101(20):2411-7. DOI: 10.1161/01.cir.101.20.2411. View

15.

Holets L, Carletti M, Kshirsagar S, Christenson L, Petroff M . Differentiation-induced post-transcriptional control of B7-H1 in human trophoblast cells. Placenta. 2008; 30(1):48-55. PMC: 2743323. DOI: 10.1016/j.placenta.2008.10.001. View

16.

Klase Z, Kale P, Winograd R, Gupta M, Heydarian M, Berro R . HIV-1 TAR element is processed by Dicer to yield a viral micro-RNA involved in chromatin remodeling of the viral LTR. BMC Mol Biol. 2007; 8:63. PMC: 1955452. DOI: 10.1186/1471-2199-8-63. View

17.

McFARLANE A, Koj A . Short-term measurement of catabolic rates using iodine-labeled plasma protein. J Clin Invest. 1970; 49(10):1903-11. PMC: 322680. DOI: 10.1172/JCI106409. View

18.

Brundert M, Heeren J, Bahar-Bayansar M, Ewert A, Moore K, Rinninger F . Selective uptake of HDL cholesteryl esters and cholesterol efflux from mouse peritoneal macrophages independent of SR-BI. J Lipid Res. 2006; 47(11):2408-21. DOI: 10.1194/jlr.M600136-JLR200. View

19.

Roberts C, Shen H, Mitchell B, Damcott C, Shuldiner A, Rodriguez A . Variants in scavenger receptor class B type I gene are associated with HDL cholesterol levels in younger women. Hum Hered. 2007; 64(2):107-13. PMC: 2861530. DOI: 10.1159/000101962. View

20.

Landschulz K, Pathak R, Rigotti A, Krieger M, Hobbs H . Regulation of scavenger receptor, class B, type I, a high density lipoprotein receptor, in liver and steroidogenic tissues of the rat. J Clin Invest. 1996; 98(4):984-95. PMC: 507514. DOI: 10.1172/JCI118883. View