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Genetic variants at the PDZ-interacting domain of the scavenger receptor class B type I interact with diet to influence the risk of metabolic syndrome in obese men and women.
Junyent M, Arnett DK, Tsai MY, Kabagambe EK, Straka RJ, Province M, An P, Lai CQ, Parnell LD, Shen J, Lee YC, Borecki I, Ordovás JM
(2009) J Nutr 139: 842-8
MeSH Terms: Adult, Binding Sites, Body Mass Index, Carrier Proteins, Diet, Dietary Fats, Female, Genetic Predisposition to Disease, Genotype, Humans, Lipids, Lipoproteins, Logistic Models, Male, Membrane Proteins, Metabolic Syndrome, Middle Aged, Obesity, Polymorphism, Single Nucleotide, Scavenger Receptors, Class B
Show Abstract · Added April 24, 2015
The scaffolding protein PDZ domain containing 1 (PDZK1) regulates the HDL receptor scavenger receptor class B type I. However, the effect of PDZK1 genetic variants on lipids and metabolic syndrome (MetS) traits remains unknown. This study evaluated the association of 3 PDZK1 single nucleotide polymorphisms (SNP) (i33968C > T, i15371G > A, and i19738C > T) with lipids and risk of MetS and their potential interactions with diet. PDZK1 SNP were genotyped in 1000 participants (481 men, 519 women) included in the Genetics of Lipid Lowering Drugs and Diet Network study. Lipoprotein subfractions were measured by proton NMR spectroscopy and dietary intake was estimated using a validated questionnaire. The PDZK1_i33968C > T polymorphism was associated with MetS (P = 0.034), mainly driven by the association of the minor T allele with higher plasma triglycerides (P = 0.004) and VLDL (P = 0.021), and lower adiponectin concentrations (P = 0.022) than in participants homozygous for the major allele (C). We found a significant gene x BMI x diet interaction, in which the deleterious association of the i33968T allele with MetS was observed in obese participants with high PUFA and carbohydrate (P-values ranging from 0.004 to 0.020) intakes. Conversely, a there was a protective effect in nonobese participants with high PUFA intake (P < 0.05). These findings suggest that PDZK1_i33968C > T genetic variants may be associated with a higher risk of exhibiting MetS. This gene x BMI x diet interaction offers the potential to identify dietary and other lifestyle changes that may obviate the onset of MetS in individuals with a specific genetic background.
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20 MeSH Terms
Impaired secretion of apolipoprotein E2 from macrophages.
Fan D, Qiu S, Overton CD, Yancey PG, Swift LL, Jerome WG, Linton MF, Fazio S
(2007) J Biol Chem 282: 13746-53
MeSH Terms: ATP Binding Cassette Transporter 1, ATP-Binding Cassette Transporters, Animals, Apolipoprotein B-100, Apolipoprotein E2, Apolipoprotein E3, Apolipoprotein E4, Carrier Proteins, Cell Line, Hepatocytes, Humans, Lentivirus, Macrophages, Peritoneal, Mice, Mutation, Missense, Protein Isoforms, Receptors, LDL, Scavenger Receptors, Class B, Transduction, Genetic
Show Abstract · Added December 10, 2013
Human apoE is a multifunctional and polymorphic protein synthesized and secreted by liver, brain, and tissue macrophages. Here we show that apoE isoforms and mutants expressed through lentiviral transduction display cell-specific differences in secretion efficiency. Whereas apoE3, apoE4, and a natural mutant of apoE4 (apoE-Cys(142)) were efficiently secreted from macrophages, apoE2 and a non-natural apoE mutant (apoE-Cys(112)/Cys(142)) were retained in the perinuclear region and only minimally secreted. The secretory block for apoE2 in macrophages was not affected by the ablation of LDLR (low density lipoprotein receptor), ABCA-1, or SR-BI (scavenger receptor class B type I) but was released in the absence of low density lipoprotein receptor related protein (LRP). In co-immunoprecipitation experiments, an anti-apoE antibody pulled down two times more LRP in apoE2-transduced macrophages than in apoE3-expressing macrophages. Non-reducing SDS-PAGE/Western blot analyses showed that macrophage apoE2 is mostly dimeric and multimeric, whereas apoE3 is predominantly monomeric. ApoE2 retention and multimer formation also occurred in human macrophages derived from the monocyte cell line THP-1. These results were specific for macrophages, as in transduced mouse primary hepatocytes: 1) ApoE2 was secreted as efficiently as apoE3 and apoE4; 2) all isoforms were exclusively in monomeric form; 3) there was no co-immunoprecipitation of apoE and LRP. A microsomal triglyceride transfer protein (MTP) inhibitor nearly deleted apoB100 secretion from hepatocytes without affecting apoE secretion. These data show that macrophages retain apoE2, a highly expressed protein carried by about 8% of the human population. Given the role of locally produced apoE in regulating cholesterol efflux, modulating inflammation, and controlling oxidative stress, this unique property of apoE2 may have important impacts on atherogenesis.
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19 MeSH Terms
Persistence of high density lipoprotein particles in obese mice lacking apolipoprotein A-I.
Gruen ML, Plummer MR, Zhang W, Posey KA, Linton MF, Fazio S, Hasty AH
(2005) J Lipid Res 46: 2007-14
MeSH Terms: Animals, Apolipoprotein A-I, CD36 Antigens, Crosses, Genetic, Gene Expression, Lipase, Lipoproteins, Lipoproteins, HDL, Lipoproteins, LDL, Liver, Mice, Mice, Inbred C57BL, Mice, Knockout, Obesity, Particle Size, RNA, Messenger, Receptors, Immunologic, Receptors, Scavenger, Scavenger Receptors, Class B
Show Abstract · Added December 10, 2013
Obese mice without leptin (ob/ob) or the leptin receptor (db/db) have increased plasma HDL levels and accumulate a unique lipoprotein referred to as LDL/HDL1. To determine the role of apolipoprotein A-I (apoA-I) in the formation and accumulation of LDL/HDL1, both ob/ob and db/db mice were crossed onto an apoA-I-deficient (apoA-I(-/-)) background. Even though the obese apoA-I(-/-) mice had an expected dramatic decrease in HDL levels, the LDL/HDL1 particle persisted. The cholesterol in this lipoprotein range was associated with both alpha- and beta-migrating particles, confirming the presence of small LDLs and large HDLs. Moreover, in the obese apoA-I(-/-) mice, LDL particles were smaller and HDLs were more negatively charged and enriched in apoE compared with controls. This LDL/HDL1 particle was rapidly remodeled to the size of normal HDL after injection into C57BL/6 mice, but it was not catabolized in obese apoA-I(-/-) mice even though plasma hepatic lipase (HL) activity was increased significantly. The finding of decreased hepatic scavenger receptor class B type I (SR-BI) protein levels may explain the persistence of LDL/HDL1 in obese apoA-I(-/-) mice. Our studies suggest that the maturation and removal of large HDLs depends on the integrity of a functional axis of apoA-I, HL, and SR-BI. Moreover, the presence of large HDLs without apoA-I provides evidence for an apoA-I-independent pathway of cholesterol efflux, possibly sustained by apoE.
1 Communities
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19 MeSH Terms
Interplay between apolipoprotein E and scavenger receptor class B type I controls coronary atherosclerosis and lifespan in the mouse.
Fazio S, Linton MF
(2005) Circulation 111: 3349-51
MeSH Terms: Animals, Apolipoproteins E, Coronary Artery Disease, Dyslipidemias, Lipid Metabolism, Lipoproteins, Longevity, Mice, Mice, Knockout, Scavenger Receptors, Class B
Added May 27, 2014
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10 MeSH Terms
Inactivation of macrophage scavenger receptor class B type I promotes atherosclerotic lesion development in apolipoprotein E-deficient mice.
Zhang W, Yancey PG, Su YR, Babaev VR, Zhang Y, Fazio S, Linton MF
(2003) Circulation 108: 2258-63
MeSH Terms: ATP Binding Cassette Transporter 1, ATP-Binding Cassette Transporters, Animals, Aorta, Apolipoproteins E, Arteriosclerosis, Blotting, Western, Bone Marrow Transplantation, CD36 Antigens, Cells, Cultured, Cholesterol, Disease Models, Animal, Disease Progression, Female, Lipoproteins, HDL, Macrophages, Peritoneal, Membrane Proteins, Mice, Mice, Inbred C57BL, Mice, Knockout, Radiation Chimera, Receptors, Immunologic, Receptors, Lipoprotein, Receptors, Scavenger, Scavenger Receptors, Class B
Show Abstract · Added December 10, 2013
BACKGROUND - Scavenger receptor class B type I (SR-BI) is expressed in macrophages, where it has been proposed to facilitate cholesterol efflux. However, direct evidence that the expression of macrophage SR-BI is protective against atherosclerosis is lacking. In this study, we examined the in vivo role of macrophage SR-BI in atherosclerotic lesion development in the apolipoprotein (apo) E-deficient mouse model.
METHODS AND RESULTS - ApoE-deficient mice with (n=16) or without (n=15) expression of macrophage SR-BI were created by transplanting lethally irradiated apoE-deficient mice with bone marrow cells collected from SR-BI-/- apoE-/- mice or SR-BI+/+ apoE-/- mice. The recipient mice were fed a chow diet for 12 weeks after transplantation for analysis of atherosclerosis. Quantification of macrophage SR-BI mRNA by real-time reverse transcription-polymerase chain reaction indicated successful engraftment of donor bone marrow and inactivation of macrophage SR-BI in recipient mice reconstituted with SR-BI-/- apoE-/- bone marrow. There were no significant differences in plasma lipid levels, lipoprotein distributions, and HDL subpopulations between the 2 groups. Analysis of the proximal aorta demonstrated an 86% increase in mean atherosclerotic lesion area in SR-BI-/- apoE-/- --> apoE-/- mice compared with SR-BI+/+ apoE-/- --> apoE-/- mice (109.50+/-18.08 versus 58.75+/-9.58x10(3) microm2; mean+/-SEM, P=0.017). No difference in cholesterol efflux from SR-BI+/+ apoE-/- or SR-BI-/- apoE-/- macrophages to HDL or apoA-I discs was detected.
CONCLUSIONS - Expression of macrophage SR-BI protects mice against atherosclerotic lesion development in apoE-deficient mice in vivo without influencing plasma lipids, HDL subpopulations, or cholesterol efflux. Thus, macrophage SR-BI plays an antiatherogenic role in vivo, providing a new therapeutic target for the design of strategies to prevent and treat atherosclerosis.
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25 MeSH Terms
Reduced atherosclerotic lesions in mice deficient for total or macrophage-specific expression of scavenger receptor-A.
Babaev VR, Gleaves LA, Carter KJ, Suzuki H, Kodama T, Fazio S, Linton MF
(2000) Arterioscler Thromb Vasc Biol 20: 2593-9
MeSH Terms: Animals, Aorta, Arteriosclerosis, Body Weight, CD36 Antigens, Cell Transplantation, Cholesterol, Diet, Atherogenic, Dietary Fats, Disease Models, Animal, Female, Fetus, Lipoproteins, Liver, Macrophages, Male, Membrane Proteins, Mice, Mice, Inbred C57BL, Receptors, Immunologic, Receptors, LDL, Receptors, Lipoprotein, Receptors, Scavenger, Scavenger Receptors, Class A, Scavenger Receptors, Class B, Time Factors, Triglycerides
Show Abstract · Added December 10, 2013
The absence of the scavenger receptor A (SR-A)-I/II has produced variable effects on atherosclerosis in different murine models. Therefore, we examined whether SR-AI/II deficiency affected atherogenesis in C57BL/6 mice, an inbred strain known to be susceptible to diet-induced atherosclerotic lesion formation, and whether the deletion of macrophage SR-AI/II expression would modulate lesion growth in C57BL/6 mice and LDL receptor (LDLR)(-/-) mice. SR-AI/II-deficient (SR-AI/II(-/-)) female and male mice on the C57BL/6 background were challenged with a butterfat diet for 30 weeks. No differences were detected in plasma lipids between SR-AI/II(-/-) and SR-AI/II(+/+) mice, whereas both female and male SR-AI/II(-/-) mice had a tremendous reduction (81% to 86%) in lesion area of the proximal aorta compared with SR-AI/II(+/+) mice. Next, to analyze the effect of macrophage-specific SR-AI/II deficiency in atherogenesis, female C57BL/6 mice were lethally irradiated, transplanted with SR-AI/II(-/-) or SR-AI/II(+/+) fetal liver cells, and challenged with the butterfat diet for 16 weeks. In a separate experiment, male LDLR(-/-) mice were reconstituted with SR-AI/II(-/-) or SR-AI/II(+/+) fetal liver cells and challenged with a Western diet for 10 weeks. No significant differences in plasma lipids and lipoprotein profiles were noted between the control and experimental groups in either experiment. SR-AI/II(-/-)-->C57BL/6 mice, however, had a 60% reduction in lesion area of the proximal aorta compared with SR-AI/II(+/+)-->C57BL/6 mice. A similar level of reduction (60%) in lesion area was noted in the proximal aorta and the entire aorta en face of SR-AI/II(-/-)-->LDLR(-/-) mice compared with SR-AI/II(+/+)-->LDLR(-/-) mice. These results demonstrate in vivo that SR-AI/II expression has no impact on plasma lipid levels and that macrophage SR-AI/II contributes significantly to atherosclerotic lesion formation.
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27 MeSH Terms
Temporal and spatial pattern of expression of the HDL receptor SR-BI during murine embryogenesis.
Hatzopoulos AK, Rigotti A, Rosenberg RD, Krieger M
(1998) J Lipid Res 39: 495-508
MeSH Terms: Animals, Biological Transport, CD36 Antigens, Carbocyanines, Cholesterol, Embryonic and Fetal Development, Female, Fluorescent Dyes, Gene Expression, Membrane Proteins, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Microscopy, Fluorescence, Placenta, Placentation, Pregnancy, Receptors, Immunologic, Receptors, Lipoprotein, Receptors, Scavenger, Scavenger Receptors, Class B, Time Factors, Yolk Sac
Show Abstract · Added June 11, 2010
During rodent fetal development, maternal lipoproteins can be sources of cholesterol for the membrane synthesis required for tissue growth in the developing embryo and for steroid hormone production in the extraembryonic tissues. Although the mechanisms underlying the maternal-fetal lipoprotein cholesterol transport system are not well defined, the placenta and yolk sac seem to play major roles in this process, serving as functionally active interfaces between maternal circulation and the embryo. In rodents, the principal cholesterol transporter in the plasma is HDL, and the HDL receptor SR-BI is a physiologically important mediator of cholesterol uptake in adult liver and steroidogenic tissues. To begin to investigate SR-BI's role in maternal cholesterol uptake by the fetus, we used immunofluorescence microscopy to determine the pattern of SR-BI expression during murine embryogenesis. At day E7.5 in gestation, there was significant SR-BI expression in endothelial cells of the decidua, but little in intraembryonic and extraembryonic tissues. By day E8.5, there was a dramatic increase in SR-BI expression in the trophoblast cells which surround the developing embryo. Beginning at day E10, SR-BI was expressed in both the placenta and yolk sac. The expression in these extraembryonic tissues was correlated with significant uptake of fluorescent dye by the yolk sac visceral endodermal cells from DiI-labeled HDL injected into pregnant mice. Within the embryo proper, SR-BI expression appeared by day E14.5 at high levels in the adrenal gland. SR-BI expression was not detected in the embryonic liver through day E17.5 of gestation; however, it could be observed in neonatal livers. These findings suggest that SR-BI may play a role in the rodent maternal-fetal lipoprotein cholesterol transport system, supplying HDL cholesterol for either membrane or steroid hormone synthesis, or both.
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23 MeSH Terms