Most epidemiological studies have shown that high density lipoprotein cholesterol (HDL) levels are inversely correlated to cardiovascular disease (CVD). Nonetheless, a subset of patients with elevated HDL (hyperalphalipoproteinemia, HA) and elevated LDL cholesterol (hyperbetalipoproteinemia, HB) levels are at increased risk for CVD. This phenotype (HA/HB) with increased risk for CVD is similar to that described in the HDL receptor, scavenger receptor, class B, type I (SR-BI) knockout mouse. In humans, polymorphisms of the SR-BI gene have been associated with HDL and LDL cholesterol levels and body mass index, but to date, no functional defects in the receptor have been reported. We have identified the first case of an adult female heterozygote for SR-BI deficiency; this was based on finding markedly lower SR-BI RNA and protein and decreased SR-BI function in the proband's macrophages, and a novel splice variant within the region of the gene that encodes the functional extracellular loop. We also found decreased SR-BI RNA expression in macrophages cultured from the proband's mother, sister, and an unrelated adult female with HA/HB. We hypothesize that mutations/polymorphisms in the SR-BI gene strongly correlate with decreased SR-BI function and are associated with HA/HB and increased risk for atherosclerosis.
The aims of this proposal are 1) to thoroughly characterize the lipoproteins and the fractional clearance of HDL-cholesteryl ester in a cohort of 40 adult subjects with HA/HB; 2) to assess SR-BI expression and function in monocyte-derived macrophages isolated from HA/HB and control subjects. The human macrophage model for SR-BI expression and function is expected to act as a surrogate for hepatic SR-BI, given the limitations in obtaining liver tissue from these donors. SR-BI knockout mice will be used to correlate changes in macrophage SR-BI expression and function with hepatic SR-BI function and to corroborate our findings in human SR-BI deficient macrophages; and 3) to identify polymorphisms and/or mutations of the SR-BI gene in HA/HB and control subjects. Transient transfection experiments with COS-7 cells will also verify the significance of SR-BI variants. This work will provide new insights into the role of SR-BI in human dyslipidemia and atherosclerosis and challenge the concept that desirable HDL cholesterol levels are always cardioprotective.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL075646-01
Application #
6720284
Study Section
Metabolism Study Section (MET)
Program Officer
Applebaum-Bowden, Deborah
Project Start
2004-04-01
Project End
2008-03-01
Budget Start
2004-04-01
Budget End
2005-03-31
Support Year
1
Fiscal Year
2004
Total Cost
$386,525
Indirect Cost
Name
Johns Hopkins University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Golden, Diana; Kolmakova, Antonina; Sura, Sunitha et al. (2016) Lymphocyte activation gene 3 and coronary artery disease. JCI Insight 1:e88628
Manichaikul, Ani; Wang, Xin-Qun; Musani, Solomon K et al. (2015) Association of the Lipoprotein Receptor SCARB1 Common Missense Variant rs4238001 with Incident Coronary Heart Disease. PLoS One 10:e0125497
DeAngelis, Anthony M; Roy-O'Reilly, Meaghan; Rodriguez, Annabelle (2014) Genetic alterations affecting cholesterol metabolism and human fertility. Biol Reprod 91:117
Manichaikul, Ani; Naj, Adam C; Herrington, David et al. (2012) Association of SCARB1 variants with subclinical atherosclerosis and incident cardiovascular disease: the multi-ethnic study of atherosclerosis. Arterioscler Thromb Vasc Biol 32:1991-9
Constantineau, Jason; Greason, Erin; West, Michael et al. (2010) A synonymous variant in scavenger receptor, class B, type I gene is associated with lower SR-BI protein expression and function. Atherosclerosis 210:177-82
Naj, Adam C; West, Michael; Rich, Stephen S et al. (2010) Association of scavenger receptor class B type I polymorphisms with subclinical atherosclerosis: the Multi-Ethnic Study of Atherosclerosis. Circ Cardiovasc Genet 3:47-52
Cherian-Shaw, Mary; Puttabyatappa, Muraly; Greason, Erin et al. (2009) Expression of scavenger receptor-BI and low-density lipoprotein receptor and differential use of lipoproteins to support early steroidogenesis in luteinizing macaque granulosa cells. Endocrinology 150:957-65
Lipari, Christopher W; Garcia, Jairo E; Zhao, Yulian et al. (2009) Nitric oxide metabolite production in the human preimplantation embryo and successful blastocyst formation. Fertil Steril 91:1316-8
West, Michael; Greason, Erin; Kolmakova, Antonina et al. (2009) 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 94:1451-7
Roberts, Caroline G P; Shen, Haiqing; Mitchell, Braxton D et al. (2007) Variants in scavenger receptor class B type I gene are associated with HDL cholesterol levels in younger women. Hum Hered 64:107-13

Showing the most recent 10 out of 12 publications