Hyperglycemia promotes overexpression of SR-BII isoform of the scavenger receptor class B type I in type 2 diabetes mellitus: A study in Juana Koslay City, San Luis, Argentina

DOI: 10.4236/jdm.2013.34027   PDF   HTML     3,340 Downloads   5,387 Views  


The scavenger receptor class B type I (SR-BI) is a high-density lipoprotein (HDL) receptor involved in reverse cholesterol transport. Some studies reported the association to be stronger in the presence of diabetes. The full length gene encoding SR-BI is comprised in 13 exons that are alternatively spliced to produce two major transcripts: the full length SR-BI and the splice variant SR-BII, in which exon 12 is skipped. Considering that type 2 diabetes status is characterized by changes in the concentration of plasma lipids, modifications in lipoprotein size and composition, which may be important modulators of the SR-BI expression; the aims of the study were to examine the influence of SR-BI polymorphism (rs838895) on lipid profile and SR-BI mRNA expression in a population of diabetic patients living in Juana Koslay City. Blood samples were drawn from controls (n = 40) and Type 2 diabetic patients (n = 66) and DNA and total RNA were obtained. SR-BI mRNA expression was measured by RT-PCR and SR-BI polymorphism was detected by Tetra Primer ARMSPCR. Compared to controls, diabetic patients had higher fasting serum glucose, glycated hemoglobin, triglycerides, total cholesterol, lowdensity lipoprotein cholesterol, and lower highdensity lipoprotein cholesterol. SR-BI mRNA expression was lower in T2DM when compared to controls, suggesting that the hyperglycemia presents in T2DM patients down-regulates SR-BI mRNA expression. Interestingly, we found that decreased SR-BI expression resulted in markedly increased plasma LDL concentrations in T2DM subjects, and the overexpression of SRBII isoform is responsible for the markedly increased plasma LDL-c concentrations. The polymorphism (rs838895) did not modify the mRNA level of SR-BI in leucocytes from control and diabetic patients. This study provides novel evidence suggesting that hyperglycemia may affect reverse cholesterol transport by controlling SRBI expression in diabetic patients. LDL cholesterol levels are associated with low SR-BI mRNA expression in T2DM. 

Share and Cite:

Mendoza, G. , Siewert, S. , González, I. , Vedova, M. , Fernandez, G. and Ojeda, M. (2013) Hyperglycemia promotes overexpression of SR-BII isoform of the scavenger receptor class B type I in type 2 diabetes mellitus: A study in Juana Koslay City, San Luis, Argentina. Journal of Diabetes Mellitus, 3, 172-183. doi: 10.4236/jdm.2013.34027.

Conflicts of Interest

The authors declare no conflicts of interest.


[1] Howard, B.V., Cowan, L.D., Go, O., Welty, T.K., Robbins, D.C. and Lee, E.T. (1998) Adverse effects of diabetes on multiple cardiovascular disease risk factors in women. The Strong Heart Study. Diabetes Care, 21, 1258-1265. http://dx.doi.org/10.2337/diacare.21.8.1258
[2] Taskinen, M.R. (2002) Diabetic dyslipidemia. Atherosclerosis, 3, 47-51.
[3] Franceschini, G. (2001) Epidemiologic evidence for highdensity lipoprotein cholesterol as a risk factor for coronary artery disease. American Journal of Cardiology, 88, 9-13.
[4] Erkelens, D.W. (2001) Insulin resistance syndrome and type 2 diabetes mellitus. American Journal of Cardiology, 88, 38-42. http://dx.doi.org/10.1016/S0002-9149(01)01883-5
[5] Ford, E.S., Giles, W.H. and Dietz, W.H. (2002) Prevalence of the metabolic syndrome among US adults: Findings from the third National Health and Nutrition Examination Survey. JAMA, 287, 356-359. http://dx.doi.org/10.1001/jama.287.3.356
[6] Stein, O. and Stein, Y. (1999) Atheroprotective mechanisms of HDL. Atherosclerosis, 144, 285-301. http://dx.doi.org/10.1016/S0021-9150(99)00065-9
[7] Silver, D.L., Jiang, X.C., Arai, T., Bruce, C. and Tall, A.R. (2000) Receptors and lipid transfer proteins in HDL metabolism. Annals of the New York Academy of Sciences, 902, 103-111.
[8] Acton, S., Rigotti, A., Landschulz, K. T., Xu, S., Hobbs, H. H. and Krieger, M. (1996) Identification of scavenger receptor SR-BI as a high density lipoprotein receptor. Science, 271, 518-520.
[9] Krieger, M. (2001) Scavenger receptor class B type I is a multiligand HDL receptor that influences diverse physiologic systems. Journal of Clinical Investigation, 108, 793-797.
[10] Rigotti, A., Miettinen, H. E. and Krieger, M. (2003) The role of the high-density lipoprotein receptor SR-BI in the lipid metabolism of endocrine and other tissues. Endocrine Reviews, 24, 357-387.
[11] Mardones, P., Quinones, V., Amigo, L., Moreno, M., Miquel, J. F., Schwarz, M., Miettinen, H. E., Trigatti, B., Krieger, M., VanPatten, S., Cohen, D. E. and Rigotti, A. (2001) Hepatic cholesterol and bile acid metabolism and intestinal cholesterol absorption in scavenger receptor class B type I-deficient mice. Journal of Lipid Research, 42, 170-180.
[12] Trigatti, B.L., Rigotti, A. and Braun, A. (2000) Cellular and physiological roles of SR-BI, a lipoprotein receptor which mediates selective lipid uptake. Biochimica et Biophysica Acta, 1529, 276-286. http://dx.doi.org/10.1016/S1388-1981(00)00154-2
[13] Brodeur, M.R., Luangrath, V., Bourret, G., Falstrault, L. and Brissette, L. (2005) Physiological importance of SR-BI in the in Vivo metabolism of human HDL and LDL in male and female mice. Journal of Lipid Research, 46, 687-696. http://dx.doi.org/10.1194/jlr.M400165-JLR200
[14] Van Eck, M., Hoekstra, M., Out, R., Bos, I.S., Kruijt, J.K., Hildebrand, R.B. and Van Berkel, T.J. (2008) Scavenger receptor BI facilitates the metabolism of VLDL lipoproteins in vivo. Journal of Lipid Research, 49, 136-146. http://dx.doi.org/10.1194/jlr.M700355-JLR200
[15] Hu, L., Hoogt van der, C.C., Espirito Santo, S.M., Out, R., Kypreos, K.E., van Vlijmen, B.J., Van Berkel, T.J., Romijn, J.A., Havekes, L.M., van Dijk, K.W., et al. (2008) The hepatic uptake of VLDL in lrp-ldlr-/-vldlr-/mice is regulated by LPL activity and involves proteoglycans and SR-BI. Journal of Lipid Research, 49, 1553-1561. http://dx.doi.org/10.1194/jlr.M800130-JLR200
[16] Eckhardt, E.R., Cai, L., Sun, B., Webb, N.R. and Westhuyzen van der, D.R. (2004) High density lipoprotein uptake by scavenger receptor SR-BII. Journal of Biological Chemistry, 279, 14372-14381. http://dx.doi.org/10.1074/jbc.M313793200
[17] Webb, N.R., Connell, P.M., Graf, G.A., Smart, E.J., de Villiers, W.J., de Beer, F.C. and Westhuyzen van der, D.R. (1998) SR-BII, an isoform of the scavenger receptor BI containing an alternate cytoplasmic tail, mediates lipid transfer between high density lipoprotein and cells. Journal of Biological Chemistry, 273, 15241-15248. http://dx.doi.org/10.1074/jbc.273.24.15241
[18] Kozarsky, K.F., Donahee, M.H., Glick, J.M., Krieger, M. and Rader, D.J. (2000) Gene transfer and hepatic overexpression of the HDL receptor SR-BI reduces atherosclerosis in the cholesterol-fed LDL receptor-deficient mouse. Arteriosclerosis, Thrombosis, and Vascular Biology, 20, 721-727.
[19] Van Eck, M., Twisk, J., Hoekstra, M., Van Rij, B.T., Van der Lans, C.A., Bos, I.S., Kruijt, J.K., Kuipers, F. and Van Berkel, T.J. (2003) Differential effects of scavenger receptor BI deficiency on lipid metabolism in cells of the arterial wall and in the liver. Journal of Biological Chemistry, 278, 23699-23705.
[20] Meigs, J.B., Shrader, P., Sullivan, L.M., McAteer, J.B., Fox, C.S., Dupuis, J., Manning, A.K., Florez, J.C., Wilson, P.W., D’Agostino Sr., R.B. and Cupples, L.A. (2008) Genotype score in addition to common risk factors for prediction of type 2 diabetes. New England Journal of Medicine, 359, 2208-2219.
[21] Florez, J.C., Hirschhorn, J. and Altshuler, D. (2003) The inherited basis of diabetes mellitus: Implications for the genetic analysis of complex traits. Annual Review of Genomics and Human Genetics, 4, 257-291. http://dx.doi.org/10.1146/annurev.genom.4.070802.110436
[22] Norris, J.M., Langefeld, C.D., Scherzinger, A.L., Rich, S.S., Bookman, E., Beck, S.R., Saad, M.F., Haffner, S.M., Bergman, R.N., Bowden, D.W. and Wagenknecht, L.E. (2005) Quantitative trait loci for abdominal fat and BMI in Hispanic-Americans and African-Americans: The IRAS Family study. International Journal of Obesity and Related Metabolic Disorders, 29, 67-77.
[23] Lewis, C.E., North, K.E., Arnett, D., Borecki, I.B., Coon, H., Ellison, R.C., Hunt, S.C., Oberman, A., Rich, S.S., Province, M.A. and Miller, M.B. (2005) Sex-specific findings from a genome-wide linkage analysis of human fatness in non-Hispanic whites and African Americans: The HyperGEN study. International Journal of Obesity (London), 29, 639-649. http://dx.doi.org/10.1038/sj.ijo.0802916
[24] Wilson, S.G., Adam, G., Langdown, M., Reneland, R., Braun, A., Andrew, T., Surdulescu, G.L., Norberg, M., Dudbridge, F., Reed, P.W., Sambrook, P.N., Kleyn, P.W. and Spector, T.D. (2006) Linkage and potential association of obesity-related phenotypes with two genes on chromosome 12q24 in a female dizygous twin cohort. European Journal of Human Genetics, 14, 340-348.
[25] Acton, S., Osgood, D., Donoghue, M., Corella, D., Pocovi, M., Cenarro, A., Mozas, P., Keilty, J., Squazzo, S., Woolf, E.A. and Ordovas, J.M. (1999) Association of polymorphisms at the SR-BI gene locus with plasma lipid levels and body mass index in a white population. Arteriosclerosis, Thrombosis, and Vascular Biology, 19, 1734-1743. http://dx.doi.org/10.1161/01.ATV.19.7.1734
[26] Yoon, Y., Song, J., Hong, S.H. and Kim, J.Q. (2003) Analysis of multiple single nucleotide polymorphisms of candidate genes related to coronary heart disease susceptibility by using support vector machines. Clinical Chemistry and Laboratory Medicine, 41, 529-534.
[27] Tai, E.S., Adiconis, X., Ordovas, J.M., Carmena-Ramon, R., Real, J., Corella, D., Ascaso, J. and Carmena, R. (2003) Polymorphisms at the SRBI locus are associated with lipoprotein levels in subjects with heterozygous familial hypercholesterolemia. Clinical Genetics, 63, 53-58.
[28] McCarthy, J.J., Lewitzky, S., Reeves, C., Permutt, A., Glaser, B., Groop, L.C., Lehner, T. and Meyer, J.M. (2003) Polymorphisms of the HDL receptor gene associated with HDL cholesterol levels in diabetic kindred from three populations. Human Heredity, 55, 163-170. http://dx.doi.org/10.1159/000073986
[29] Hong, S.H., Kim, Y.R., Yoon, Y.M., Min, W.K., Chun, S.I. and Kim, J.Q. (2002) Association between Hae III polymorphism of scavenger receptor class B type I gene and plasma HDL-cholesterol concentration. Annals of Clinical Biochemistry, 39, 478-481. http://dx.doi.org/10.1258/ 000456302320314485
[30] Richard, E., von Muhlen, D., Barrett-Connor, E., Alcaraz, J., Davis, R. and McCarthy, J.J. (2005) Modification of the effects of estrogen therapy on HDL cholesterol levels by polymorphisms of the HDL-C receptor, SR-BI: The Rancho Bernardo Study. Atherosclerosis, 180, 255-262.
[31] Hsu, L.A., Ko, Y.L., Wu, S., Teng, M.S., Peng, T.Y., Chen, C.F. and Lee, Y.S. (2003) Association between a novel 11-base pair deletion mutation in the promoter region of the scavenger receptor class B type I gene and plasma HDL cholesterol levels in Taiwanese Chinese. Arteriosclerosis, Thrombosis, and Vascular Biology, 23, 1869-1874. http://dx.doi.org/10.1161/01.ATV. 0000082525.84814.A9
[32] Morabia, A., Ross, B.M., Costanza, M.C., Cayanis, E., Flaherty, M.S., Alvin, G.B., Das, K., James, R., Yang, A.S., Evagrafov, O. and Gilliam, T.C. (2004) Populationbased study of SR-BI genetic variation and lipid profile. Atherosclerosis, 175, 159-168. http://dx.doi.org/10.1016/j.atherosclerosis. 2004.03.014
[33] Roberts, C.G., Shen, H., Mitchell, B.D., Damcott, C.M., Shuldiner, A.R. and Rodriguez, A. (2007) Variants in scavenger receptor class B type I gene are associated with HDL cholesterol levels in younger women. Human Heredity, 64, 107-113. http://dx.doi.org/10.1159/000101962
[34] Osgood, D., Corella, D., Demissie, S., Cupples, L.A., Wilson, P.W., Meigs, J.B., Schaefer, E.J., Coltell, O. and Ordovas, J.M. (2003) Genetic variation at the scavenger receptor class B type I gene locus determines plasma lipoprotein concentrations and particle size and interacts with type 2 diabetes: The Framingham Study. Journal of Clinical Endocrinology & Metabolism, 88, 2869-2879.
[35] Chiba-Falek, O., Nichols, M., Suchindran, S., Guyton, J., Ginsburg, G.S., Barrett-Connor, E. and McCarthy, J.J. (2010) Impact of gene variants on sex-specific regulation of human Scavenger receptor class B type 1(SR-BI) expression in liver and association with lipid levels in a population-based study. BMC Medical Genetics, 19, 9. http://dx.doi.org/10.1186/1471-2350-11-9
[36] Goff Jr., D.C., D’Agostino Jr., R.B., Haffner, S.M., Saad, M.F. and Wagenknecht, L.E. (2000) Lipoprotein concentrations and carotid atherosclerosis by diabetes status: Results from the insulin resistance atherosclerosis study. Diabetes Care, 23, 1006-1011. http://dx.doi.org/10.2337/diacare.23.7.1006
[37] Tan, K.C., Ai, V.H., Chow, W.S., Chau, M.T., Leong, L. and Lam, K.S. (1999) Influence of low density lipoprotein (LDL) subfraction profile and LDL oxidation on endothelium dependent and independent vasodilation in patients with type 2 diabetes. Journal of Clinical Endocrinology & Metabolism, 84, 3212-3216. http://dx.doi.org/10.1210/jc.84.9.3212
[38] The Expert Committee of the Diagnosis and Classification of Diabetes Mellitus (1997) Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Diabetes Care, 20, 1183-1197.
[39] Friedewald, W.T., Levy, R.I. and Fredrickson, D.S. (1972) Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clinical Chemistry, 18, 499-502.
[40] Ye, S., Dhillon, S., Ke, X., Collins, A.R. and Day, I.N. (2001) An efficient procedure for genotyping single nucleotide polymorphisms. Nucleic Acids Research, 29, E88. http://dx.doi.org/10.1093/nar/ 29.17.e88
[41] Perez-Martinez, P., Ordovas, J.M., Lopez-Miranda, J., Gomez, P., Marin, C., Moreno, J., Fuentes, F., Fernandez de la Puebla, R.A. and Perez-Jimenez, F. (2003) Polymorphism exon 1 variant at the locus of the scavenger receptor class B type I gene: Influence on plasma LDL cholesterol in healthy subjects during the consumption of diets with different fat contents. American Journal of Clinical Nutrition, 77, 809-813.
[42] Acton, S.L., Scherer, P.E., Lodish, H.F. and Kreiger, M. (1994) Expression cloning of SR-BI, a CD36-related Class B Scavenger Receptor. Journal of Biological Chemistry, 269, 21003-21009.
[43] Calvo, D., Gomez-Coronado, D., Lasuncion, M.A. and Vega, M.A. (1997) CLA-1 is an 85-kD plasma membrane glycoprotein that acts as a high-affinity receptor for both native (HDL, LDL, and VLDL) and modified (OxLDL and AcLDL) lipoproteins. Arteriosclerosis, Thrombosis, and Vascular Biology, 17, 2341-2349. http://dx.doi.org/10.1161/01.ATV.17.11.2341
[44] Wang, N., Arai, T., Ji, Y., Rinninger, F. and Tall, A.R. (1998) Liverspecific overexpression of scavenger recaptor BI decreases levels of very low density lipoprotein apoB, low density lipoprotein apoB, and high density lipoprotein in transgenic mice. Journal of Biological Chemistry, 273, 32920-32926.
[45] Ueda, Y., Royer, L., Gong, E., Zhang, J., Cooper, P.N., Francone, O. and Rubin, E.M. (1999) Lower plasma levels and accelerated clearance of high density lipoprotein (HDL) and non-HDL cholesterol in scavenger receptor class B Type I transgenic mice. Journal of Biological Chemistry, 274, 7165-7171. http://dx.doi.org/10.1074/jbc.274.11.7165
[46] Zhang, X., Merkler, K.A. and McLean, M.P. (2008) Characterization of regulatory intronic and exonic sequences involved in alternative splicing of scavenger receptor class B gene. Biochemical and Biophysical Research Communications, 372, 173-178. http://dx.doi.org/10.1016/j.bbrc.2008.05.007
[47] Powell, E.E. and Kroon, P.A. (1994) Low density lipoprotein receptor and 3-hydroxy-3-methylglutaryl coenzyme A reductase gene expression in human mononuclear leukocytes is regulated coordinately and parallels gene expression in human liver. Journal of Clinical Investigation, 93, 2168-2174.
[48] Murao, K., Yu, X., Imachi, H., Cao, W.M., Chen, K., Matsumoto, K., Nishiuchi, T., Wong, N.C. and Ishida, T. (2008) Hyperglycemia suppresses hepatic scavenger receptor class B type I expression. American Journal of Physiology, Endocrinology and Metabolism, 294, E78-E87.
[49] Ravid, Z., Bendayan, M., Delvin, E., Sane, A.T., Elchebly, M., Lafond, J., Lambert, M., Mailhot, G. and Levy, E. (2008) Modulation of intestinal cholesterol absorption by high glucose levels: Impact on cholesterol transporters, regulatory enzymes, and transcription factors. American Journal of Physiology, Gastrointestinal and Liver Physiology, 295, G873-G885.
[50] Swarnakar, S., Temel, R.E., Connelly, M.A., Azhar, S. and Williams, D.L. (1999) Scavenger receptor class B, type I, mediates selective uptake of low density lipoprotein cholesteryl ester. Journal of Biological Chemistry, 274, 29733-29739. http://dx.doi.org/10.1074/jbc.274.42.29733
[51] Stangl, H., Hyatt, M. and Hobbs, H.H. (1999) Transport of lipids from high and low density lipoproteins via scavenger receptor-BI. Journal of Biological Chemistry, 274, 32692-32698.
[52] Cuchel, M., Lund-Katz, S., de la Llera-Moya, M., Millar, J.S., Chang, D., Fuki, I., Rothblat, G.H., Phillips, M.C. and Rader, D.J. (2010) Pathways by which reconstituted high-density lipoprotein mobilizes free cholesterol from whole body and from macrophages. Arteriosclerosis, Thrombosis, and Vascular Biology, 30, 526-532. http://dx.doi.org/10.1161/ATVBAHA.109.196105
[53] Rhainds, D., Brodeur, M., Lapointe, J., Charpentier, D., Falstrault, L. and Brissette, L. (2003) The role of human and mouse hepatic scavenger receptor class B type I (SR-BI) in the selective uptake of low-density lipoprotein-cholesteryl esters. Biochemistry, 42, 7527-7538.
[54] Landschulz, K.T., Pathak, R.K., Rigotti, A., Krieger, M. and Hobbs, H.H. (1996) Regulation of scavenger receptor, class B, type I, a high density lipoprotein receptor, in liver and steroidogenic tissues of the rat. Journal of Clinical Investigation, 98, 984-995. http://dx.doi.org/10.1172/JCI118883
[55] Greene, D.J., Skeggs, J.W. and Morton, R.E. (2001) Elevated triglyceride content diminishes the capacity of high density lipoprotein to deliver cholesteryl esters via the scavenger receptor class B type I (SR-BI). Journal of Clinical Investigation, 276, 4804-4811.
[56] Gillotte-Taylor, K., Boullier, A., Witztum, J.L., Steinberg, D. and Quehenberger, O. (2001) Scavenger receptor class B type I as a receptor for oxidized low density lipoprotein. Journal of Lipid Research, 42, 1474-1482.
[57] Iwashima, Y., Eto, M., Hata, A., Kaku, K., Horiuchi, S., Ushikubi, F. and Sano, H. (2000) Advanced glycation end products-induced gene expression of scavenger receptors in cultured human monocyte-derived macrophages. Biochemical and Biophysical Research Communications, 277, 368-380.
[58] Lopez, D. and McLean, M.P. (2006) Estrogen regulation of the scavenger receptor class B gene: Anti-atherogenic or steroidogenic, is there a priority? Molecular and Cellular Endocrinology, 247, 22-33. http://dx.doi.org/10.1016/j.mce.2005.10.005
[59] Zhang, X., Moor, A.N., Merkler, K.A., Liu, Q. and McLean, M.P. (2007) Regulation of alternative splicing of liver scavenger receptor class B gene by estrogen and the involved regulatory splicing factors. Endocrinology, 148, 5295-5304. http://dx.doi.org/10.1210/en.2007-0376
[60] Graf, G.A., Roswell, K.L. and Smart, E.J. (2001) 17betaestradiol promotes the upregulation of SR-BII in HepG2 cells and in rat livers. Journal of Lipid Research, 42, 1444-1449.
[61] Webb, N.R., Connell, P.M., Graf, G.A., Smart, E.J., de Villiers, W.J., de Beer, F.C. and Westhuyzen van der, D.R. (1998) SR-BII, an isoform of the scavenger receptor BI containing an alternate cytoplasmic tail, mediates lipid transfer between high density lipoprotein and cells. Journal of Biological Chemistry, 273, 15241-15248. http://dx.doi.org/10.1074/jbc.273.24.15241

comments powered by Disqus

Copyright © 2020 by authors and Scientific Research Publishing Inc.

Creative Commons License

This work and the related PDF file are licensed under a Creative Commons Attribution 4.0 International License.