2013/07/01 by Xiao Yang, Xiao-Ping Yang, Marcelo J. Amar +10 · 26 citations
Medicine · Biochemistry, Genetics and Molecular Biology · #Lipoproteins and Cardiovascular Health #Cholesterol and Lipid Metabolism #Cancer, Lipids, and Metabolism
paper · doi:10.1194/jlr.m038877
Scavenger receptor class B type I (SR-BI) is a multi-ligand receptor that binds a variety of lipoproteins, including high density lipoprotein (HDL) and low density lipoprotein (LDL), but lipoprotein(a) [Lp(a)] has not been investigated as a possible ligand. Stable cell lines (HEK293 and HeLa) expressing human SR-BI were incubated with protein- or lipid-labeled Lp(a) to investigate SR-BI-dependent Lp(a) cell association. SR-BI expression enhanced the association of both 125I- and Alexa Fluor-labeled protein from Lp(a). By confocal microscopy, SR-BI was also found to promote the internalization of fluorescent lipids (BODIPY-cholesteryl ester (CE)- and DiI-labeled) from Lp(a), and by immunocytochemistry the cellular internalization of apolipoprotein(a) and apolipoprotein B. When dual-labeled (3H-cholesteryl ether,125I-protein) Lp(a) was added to cells expressing SR-BI, there was a greater relative increase in lipid uptake over protein, indicating that SR-BI mediates selective lipid uptake from Lp(a). Compared with C57BL/6 control mice, transgenic mice overexpressing human SR-BI in liver were found to have increased plasma clearance of 3H-CE-Lp(a), whereas mouse scavenger receptor class B type I knockout (Sr-b1-KO) mice had decreased plasma clearance (fractional catabolic rate: 0.63 ± 0.08/day, 1.64 ± 0.62/day, and 4.64 ± 0.40/day for Sr-b1-KO, C57BL/6, and human scavenger receptor class B type I transgenic mice, respectively). We conclude that Lp(a) is a novel ligand for SR-BI and that SR-BI mediates selective uptake of Lp(a)-associated lipids. Scavenger receptor class B type I (SR-BI) is a multi-ligand receptor that binds a variety of lipoproteins, including high density lipoprotein (HDL) and low density lipoprotein (LDL), but lipoprotein(a) [Lp(a)] has not been investigated as a possible ligand. Stable cell lines (HEK293 and HeLa) expressing human SR-BI were incubated with protein- or lipid-labeled Lp(a) to investigate SR-BI-dependent Lp(a) cell association. SR-BI expression enhanced the association of both 125I- and Alexa Fluor-labeled protein from Lp(a). By confocal microscopy, SR-BI was also found to promote the internalization of fluorescent lipids (BODIPY-cholesteryl ester (CE)- and DiI-labeled) from Lp(a), and by immunocytochemistry the cellular internalization of apolipoprotein(a) and apolipoprotein B. When dual-labeled (3H-cholesteryl ether,125I-protein) Lp(a) was added to cells expressing SR-BI, there was a greater relative increase in lipid uptake over protein, indicating that SR-BI mediates selective lipid uptake from Lp(a). Compared with C57BL/6 control mice, transgenic mice overexpressing human SR-BI in liver were found to have increased plasma clearance of 3H-CE-Lp(a), whereas mouse scavenger receptor class B type I knockout (Sr-b1-KO) mice had decreased plasma clearance (fractional catabolic rate: 0.63 ± 0.08/day, 1.64 ± 0.62/day, and 4.64 ± 0.40/day for Sr-b1-KO, C57BL/6, and human scavenger receptor class B type I transgenic mice, respectively). We conclude that Lp(a) is a novel ligand for SR-BI and that SR-BI mediates selective uptake of Lp(a)-associated lipids. Scavenger receptor class B type I (SR-BI) is a multi-ligand receptor. It binds a variety of oxidized as well as native lipoproteins, including high density lipoprotein (HDL) and low density lipoprotein (LDL) (1Rhainds D. Brissette L. The role of scavenger receptor class B type I (SR-BI) in lipid trafficking. Defining the rules for lipid traders.Int. J. Biochem. Cell Biol. 2004; 36: 39-77Crossref PubMed Scopus (131) Google Scholar, 2Acton S. Rigotti A. Landschulz K.T. Xu S. Hobbs H.H. Krieger M. Identification of scavenger receptor SR-BI as a high density lipoprotein receptor.Science. 1996; 271: 518-520Crossref PubMed Scopus (1999) Google Scholar, 3Murao K. Terpstra V. Green S.R. Kondratenko N. Steinberg D. Quehenberger O. Characterization of CLA-1, a human homologue of rodent scavenger receptor BI, as a receptor for high density lipoprotein and apoptotic thymocytes.J. Biol. Chem. 1997; 272: 17551-17557Abstract Full Text Full Text PDF PubMed Scopus (288) Google Scholar–4Wang N. Arai T. Ji Y. Rinninger F. Tall A.R. Liver-specific overexpression of scavenger receptor BI decreases levels of very low density lipoprotein ApoB, low density lipoprotein ApoB, and high density lipoprotein in transgenic mice.J. Biol. Chem. 1998; 273: 32920-32926Abstract Full Text Full Text PDF PubMed Scopus (245) Google Scholar). SR-BI preferentially mediates the cellular uptake of neutral lipids over protein from lipoproteins by a process termed selective uptake. In the liver, the selective uptake of cholesteryl esters (CEs) from HDL potentiates the reverse cholesterol transport pathway, by increasing the hepatic excretion of cholesterol (5Rader D.J. Alexander E.T. Weibel G.L. Billheimer J. Rothblat G.H. The role of reverse cholesterol transport in animals and humans and relationship to atherosclerosis.J. Lipid Res. 2009; 50 (Suppl.): S189-S194Abstract Full Text Full Text PDF PubMed Scopus (452) Google Scholar). Lipoprotein(a) [Lp(a)] is a pro-atherogenic lipoprotein particle that contains one copy of apolipoprotein(a) [apo(a)] covalently linked to apoB-100 by a disulfide bond. It is found in some primates but is not present in most other mammalian species (6Utermann G. The mysteries of lipoprotein(a).Science. 1989; 246: 904-910Crossref PubMed Scopus (1098) Google Scholar). Variation in the plasma level of Lp(a) is largely under genetic control, with polymorphisms in the kringle 4 repeat of apo(a) accounting for 40% of the variation (7Gavish D. Azrolan N. Breslow J.L. Plasma lp(a) concentration is inversely correlated with the ratio of Kringle IV/Kringle V encoding domains in the apo(a) gene.J. Clin. Invest. 1989; 84: 2021-2027Crossref PubMed Scopus (142) Google Scholar). In general, apo(a) size is inversely associated with plasma Lp(a) level, but the relationship between apo(a) size and Lp(a) concentration varies among ethnic groups (8Lanktree M.B. Anand S.S. Yusuf S. Hegele R.A. Comprehensive analysis of genomic variation in the LPA locus and its relationship to plasma lipoprotein(a) in South Asians, Chinese, and European Caucasians.Circ. Cardiovasc. Genet. 2010; 3: 39-46Crossref PubMed Scopus (97) Google Scholar). In addition, a pentanucleotide repeat polymorphism in the 5′ control region of apo(a) accounts for 10–14% of the variation in Lp(a) concentrations in Caucasians (9Trommsdorff M. Kochl S. Lingenhel A. Kronenberg F. Delport R. Vermaak H. Lemming L. Klausen I.C. Faergeman O. Utermann G. et al.A pentanucleotide repeat polymorphism in the 5′ control region of the apolipoprotein(a) gene is associated with lipoprotein(a) plasma concentrations in Caucasians.J. Clin. Invest. 1995; 96: 150-157Crossref PubMed Scopus (141) Google Scholar). Human tracer studies have shown that plasma concentrations of Lp(a) were not only positively correlated with the secretion rates of Lp(a) protein, but also negatively correlated with the fractional catabolic rates (FCRs) of Lp(a) proteins, both apo(a) and apoB-100, indicating that plasma Lp(a) levels are also regulated by its rate of catabolism (10Jenner J.L. Seman L.J. Millar J.S. Lamon-Fava S. Welty F.K. Dolnikowski G.G. Marcovina S.M. Lichtenstein A.H. Barrett P.H. deLuca C. et al.The metabolism of apolipoproteins (a) and B-100 within plasma lipoprotein (a) in human beings.Metabolism. 2005; 54: 361-369Abstract Full Text Full Text PDF PubMed Scopus (52) Google Scholar). However, the receptors that bind and mediate the catabolism of Lp(a) are not well characterized. Although Lp(a) is structurally and compositionally similar to LDL, it is known to be a relatively poor ligand for the LDL receptor (11Rader D.J. Mann W.A. Cain W. Kraft H.G. Usher D. Zech L.A. Hoeg J.M. Davignon J. Lupien P. Grossman M. et al.The low density lipoprotein receptor is not required for normal catabolism of Lp(a) in humans.J. Clin. Invest. 1995; 95: 1403-1408Crossref PubMed Scopus (176) Google Scholar), as well as for the lipoprotein receptor-related protein (12Reblin T. Niemeier A. Meyer N. Willnow T.E. Kronenberg F. Dieplinger H. Greten H. Beisiegel U. Cellular uptake of lipoprotein[a] by mouse embryonic fibroblasts via the LDL receptor and the LDL receptor-related protein.J. Lipid Res. 1997; 38: 2103-2110Abstract Full Text PDF PubMed Google Scholar). Lp(a) can bind to the VLDL receptor, but mice defective in this receptor showed only a modest delay in the catabolism of heterologous Lp(a) (13Argraves K.M. Kozarsky K.F. Fallon J.T. Harpel P.C. Strickland D.K. The atherogenic lipoprotein Lp(a) is internalized and degraded in a process mediated by the VLDL receptor.J. Clin. Invest. 1997; 100: 2170-2181Crossref PubMed Scopus (130) Google Scholar), suggesting the presence of other receptor(s). Because of the close structural similarity of Lp(a) with LDL, a known ligand for SR-BI (1Rhainds D. Brissette L. The role of scavenger receptor class B type I (SR-BI) in lipid trafficking. Defining the rules for lipid traders.Int. J. Biochem. Cell Biol. 2004; 36: 39-77Crossref PubMed Scopus (131) Google Scholar, 2Acton S. Rigotti A. Landschulz K.T. Xu S. Hobbs H.H. Krieger M. Identification of scavenger receptor SR-BI as a high density lipoprotein receptor.Science. 1996; 271: 518-520Crossref PubMed Scopus (1999) Google Scholar, 3Murao K. Terpstra V. Green S.R. Kondratenko N. Steinberg D. Quehenberger O. Characterization of CLA-1, a human homologue of rodent scavenger receptor BI, as a receptor for high density lipoprotein and apoptotic thymocytes.J. Biol. Chem. 1997; 272: 17551-17557Abstract Full Text Full Text PDF PubMed Scopus (288) Google Scholar–4Wang N. Arai T. Ji Y. Rinninger F. Tall A.R. Liver-specific overexpression of scavenger receptor BI decreases levels of very low density lipoprotein ApoB, low density lipoprotein ApoB, and high density lipoprotein in transgenic mice.J. Biol. Chem. 1998; 273: 32920-32926Abstract Full Text Full Text PDF PubMed Scopus (245) Google Scholar), we investigated in this study whether SR-BI can also serve as a receptor for Lp(a). Human SR-BI cDNA, generated by RT-PCR from total RNA of human monocytes, was inserted into a pcDNA3 vector (Invitrogen, Carlsbad, CA) and sequence confirmed. HEK293 and HeLa cells were purchased from American Type Culture Collection. Cells were cultured in DMEM growth medium (DMEM, 4 mM glutamine, 10% fetal bovine serum, 100 u/ml penicillin, and 100 μg/ml streptomycin). The SR-BI cDNA-containing plasmid was transfected into 80% confluent HEK293 and HeLa cells (14Vishnyakova T.G. Bocharov A.V. Baranova I.N. Chen Z. Remaley A.T. Csako G. Eggerman T.L. Patterson A.P. Binding and internalization of lipopolysaccharide by Cla-1, a human orthologue of rodent scavenger receptor B1.J. Biol. Chem. 2003; 278: 22771-22780Abstract Full Text Full Text PDF PubMed Scopus (122) Google Scholar) using Effectene transfection reagent (Qiagen, Valencia, CA). Cell clones were selected in DMEM growth medium containing 2 mg/ml G418 for 2 weeks and maintained with 0.25 mg/ml G418. To verify SR-BI expression, cells before or after transfection were lysed and analyzed by Western blotting with rabbit anti-human polyclonal SR-BI or rabbit anti-human polyclonal VLDL receptor antibodies (Abcam, Cambridge, UK). Western blotting was performed as previously described (15Yang X.P. Mattagajasingh S. Su S. Chen G. Cai Z. Fox-Talbot K. Irani K. Becker L.C. Fractalkine upregulates intercellular adhesion molecule-1 in endothelial cells through CX3CR1 and the Jak Stat5 pathway.Circ. Res. 2007; 101: 1001-1008Crossref PubMed Scopus (54) Google Scholar). 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Lp(a), in cell was prepared as previously described of lipoprotein (a) after and density 1996; PubMed Google Scholar). human donor was to a density of with and for to a containing cholesteryl ester protein was with and under in a of mM mM and 2 mM and the was Lp(a) was added to of the containing of the was and incubated under The Lp(a) was in to a density of and for to lipid The was and to a density of and for The the was with The of the Lp(a) were Lp(a) dual-labeled Lp(a), Lp(a) was with by Lp(a), for studies in mice was generated as previously described Zech L.A. J. J.M. et of the cholesterol from LDL cholesteryl ester is defective in in normal metabolism of HDL and LDL from the Lipid Res. 1997; 38: Full Text PDF PubMed Google Scholar). and of American was under in of and added over to the lipoprotein mg/ml protein with and as previously described Zech L.A. J. J.M. et of the cholesterol from LDL cholesteryl ester is defective in in normal metabolism of HDL and LDL from the Lipid Res. 1997; 38: Full Text PDF PubMed Google Scholar). was by and analyzed by to of the HDL to and LDL to were by density as previously described T.G. of plasma lipoproteins by Biochem. PubMed Scopus Google Scholar) and within of To cellular Lp(a) cell association using HEK293 cells to in were incubated with the concentration of for in the of Lp(a) total cell or in the presence of a of Lp(a) cell Cells were with and with and cell association was by cell association from total cell association and as cellular To cellular Lp(a) cell association by HEK293 cells were incubated with μg/ml Alexa Lp(a) in DMEM containing 2 mg/ml and mM for Cells were with with a cell with in and analyzed by a cell To cellular Lp(a) cell association by confocal microscopy, HeLa cells were incubated with μg/ml Alexa Lp(a) in DMEM containing 2 mg/ml and mM for by a Lp(a) for and by confocal the HDL and LDL were prepared by density using human donor and within of To the protein of lipoproteins to protein concentrations of LDL, Lp(a), and HDL were by the using as the concentrations were using protein of for LDL for Lp(a) one and for HDL protein of Lipid the for and fluorescent HEK293 cells expressing SR-BI were incubated with Lp(a) in the presence or of or for by the or the concentrations were added to the cell medium with and incubated with the cells for Cells were with and cell as prepared were to protein and lipid uptake. Lp(a) was prepared as previously described L. S. in the transport of cholesteryl Biol. Chem. 1996; 271: Full Text Full Text PDF PubMed Scopus Google Scholar). of was with of and and under in of the of fluorescent lipids was added to of Lp(a) in 2 of containing with 4 and for The was by of the for and and lipoprotein was prepared as previously described T.L. lipoproteins to fibroblasts from in by PubMed Google Scholar). of Lp(a) was with K. Terpstra V. Green S.R. Kondratenko N. Steinberg D. Quehenberger O. Characterization of CLA-1, a human homologue of rodent scavenger receptor BI, as a receptor for high density lipoprotein and apoptotic thymocytes.J. Biol. Chem. 1997; 272: 17551-17557Abstract Full Text Full Text PDF PubMed Scopus (288) Google Scholar), concentration 100 2 of and 100 μg/ml and The Lp(a) was to a density of with and for to The was and To cellular uptake of fluorescent HeLa cells transfected with vector or with SR-BI were with mg/ml in in DMEM with for the cells were with medium with μg/ml Lp(a) for or The medium was and the were with and with and the were under a confocal anti-human polyclonal apo(a) was purchased from Meridian Life and anti-human polyclonal from and The antibodies for were with the Alexa or HeLa cells were cultured in DMEM medium with for the was with DMEM 2 mg/ml and mM with Lp(a) concentration and cells were incubated for 2 the cells were with for and with for was performed with the the cells were incubated with μg/ml Lp(a) for and incubated for 2 The cells were and incubated with antibodies for 2 by with and was by the of the protein containing into the cell as previously described J.L. of lipoprotein in cultured PubMed Scopus Google Scholar). 0.25 of was added to of medium in a the was incubated for and to was with of 40% by of of was added and to The was and was to the of in cell was The expression vector J. J. A. J.M. of hepatic in transgenic to a of plasma high density lipoproteins and density PubMed Scopus Google Scholar) was to mice expressing human SR-BI The human SR-BI was by I and inserted into the I of and clones were after with I and The was with I and and a containing the expression was from a and by density mM and mM the was into of from and expression analysis of the transgenic mice was performed as previously described M. C. Remaley A.T. expression of human in mice plasma HDL cholesterol and atherosclerosis.J. Lipid Res. Full Text Full Text PDF PubMed Scopus Google Scholar). of mice containing of the human SR-BI gene was to a of human SR-BI transgenic to N. Arai T. Ji Y. Rinninger F. Tall A.R. Liver-specific overexpression of scavenger receptor BI decreases levels of very low density lipoprotein ApoB, low density lipoprotein ApoB, and high density lipoprotein in transgenic mice.J. Biol. Chem. 1998; 273: 32920-32926Abstract Full Text Full Text PDF PubMed Scopus (245) Google Scholar), the mice had decreased plasma levels of HDL cholesterol with control mice C57BL/6 ± of was into the of C57BL/6 mice mouse scavenger receptor class B type I knockout (Sr-b1-KO) mice and mice 50 of was the and plasma was and for in a Plasma for were generated by the plasma by the plasma the not among the study groups The was from the under the plasma using a the were performed using CA). are as the ± of and the shown or was for and was By Western HEK293 and HeLa cells not of SR-BI or VLDL receptor as previously W. S. A. M. J. H. J. The low density lipoprotein receptor gene expression of receptors in the Biol. Chem. 1998; 273: Full Text Full Text PDF PubMed Scopus Google Scholar). transfection with human SR-BI cDNA, both cell lines increased of SR-BI protein SR-BI was not by confocal in HEK293 or HeLa cells after with a rabbit anti-human SR-BI polyclonal In transfected HEK293 and HeLa cells showed for SR-BI, was present the cell but also in in the of HeLa Compared with control HEK293 a HEK293 cell expressing human SR-BI showed a to increase in its association with Lp(a), in its protein by by transfected HEK293 cells showed increased association with Lp(a) protein with control cells transfected HeLa cells expressing SR-BI, were HEK293 cells for by confocal microscopy, also associated with increased of Lp(a) that was in its protein by Alexa Lp(a) be in SR-BI transfected HeLa cells but not in HeLa cells or in HeLa cells transfected with the human LDL receptor of Lp(a), or LDL the association of Lp(a) protein with HEK293 cells transfected with SR-BI were Lp(a), or LDL were to for association of Lp(a) with a of LDL was found to be the other lipoproteins The uptake of the lipid and protein of Lp(a) by cells was investigated by confocal HeLa cells with Lp(a) with for a neutral or K. Terpstra V. Green S.R. Kondratenko N. Steinberg D. Quehenberger O. Characterization of CLA-1, a human homologue of rodent scavenger receptor BI, as a receptor for high density lipoprotein and apoptotic thymocytes.J. Biol. Chem. 1997; 272: 17551-17557Abstract Full Text Full Text PDF PubMed Scopus (288) Google for a a uptake of both fluorescent lipids was of fluorescent lipids were in the and and In lipid uptake was in control cells after with Lp(a), HeLa cells were with or antibodies and apo(a) was only in HeLa cells transfected with SR-BI and not in control cells When cells were directly with both antibodies of the was in the region HEK293 cells were incubated with μg/ml of dual-labeled Lp(a) Compared with cells HEK293 cells expressing SR-BI showed a increase in the association of Lp(a) Although cells also showed increase in the association of Lp(a) protein, the increase in protein relative to control cells was not as The level of associated with the SR-BI cells also a 2 whereas the cellular uptake of from Lp(a) to increase over the of degraded Lp(a) protein were in the cell from cell In to investigate the of SR-BI to with Lp(a) in was into lines of mice with levels of SR-BI, control C57BL/6 mice, mice, and mice, the human SR-BI in the liver of C57BL/6 increase in the plasma clearance of was in the mice with the control mice In a delay in the plasma clearance of was in mice with the control C57BL/6 from this study is that Lp(a) is a ligand for the SR-BI receptor. was shown to in cell HEK293 cells and HeLa cell lines transfected with SR-BI showed increased association of Lp(a) was for both the lipid and protein of Lp(a). the studies of the lipoproteins with Lp(a) for SR-BI was not SR-BI is a scavenger receptor and is known to bind to LDL and LDL was the Lp(a) as a that there be a possible of the apo(a) of Lp(a) with SR-BI, is in from this study is that SR-BI can promote the selective lipid uptake of from Lp(a), as it from other lipoproteins H. 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Although SR-BI was found to mediate the cellular uptake of the protein and lipid of Lp(a) it to preferentially promote the uptake of a neutral lipid When cells were incubated with dual-labeled Lp(a), a greater relative increase in the uptake of was over the protein some and apo(a) protein be in cells with control cells of Lp(a) protein were The cell that SR-BI can serve as a receptor for Lp(a) were in plasma studies in mice mice, with increased expression of hepatic SR-BI, showed increased clearance of plasma with C57BL/6 mice, whereas mice had decreased not Lp(a), but the of hepatic levels of SR-BI in mice in in the catabolism of added Lp(a) in a the cell It is to that there was a delay in Lp(a) catabolism in mice, of the was from the plasma of mice after that there are other receptors for Lp(a) catabolism from the Compared with LDL, Lp(a) is present in the plasma a concentration (6Utermann G. 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The role of oxidized in lipoprotein(a) PubMed Scopus Google Scholar). The of oxidized lipids to cells is to be Usher D.J. in of role for endothelial cells in J. 1995; Google Scholar, G. P. S. F. G. gene expression by lipid in the of Biol. PubMed Scopus Google Scholar). of from oxidized lipoproteins have been shown to be for selective lipid uptake by SR-BI K. W. Scavenger receptor BI mediates the selective uptake of oxidized cholesterol esters by Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). the of oxidized cholesterol gene and the of oxidized lipids from Lp(a) to cells by SR-BI be a to the of Lp(a). The atherogenic from Lp(a) is in to its plasma level, is known to be inversely to the size of its apo(a) A. lipoprotein(a) levels and PubMed Scopus Google Scholar). apo(a) to the of Lp(a) to SR-BI and whether size of apo(a) can also the of Lp(a) to SR-BI is not known but also be of In SR-BI was found to bind and promote the cellular uptake of Lp(a). In SR-BI was found to the selective lipid uptake of from Lp(a). a possible role for SR-BI as a receptor for Lp(a) and novel for the atherogenic of Lp(a). The the and for the of confocal cholesteryl ester cholesteryl cholesteryl ester protein fractional catabolic rate human scavenger receptor class B type I transgenic lipoprotein(a) human scavenger receptor class B type I mouse scavenger receptor class B type I knockout