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Theo J.c. Van Berkel - One of the best experts on this subject based on the ideXlab platform.
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adrenal specific Scavenger Receptor BI deficiency induces glucocorticoid insufficiency and lowers plasma very low density and low density lipoprotein levels in mice
Arteriosclerosis Thrombosis and Vascular Biology, 2013Co-Authors: Menno Hoekstra, Miranda Van Eck, Ronald J Van Der Sluis, Theo J.c. Van BerkelAbstract:Objective— We determined the physiological consequences of adrenocortical-specific deletion of Scavenger Receptor BI (SR-BI) function in C57BL/6 wild-type mice. Methods and Results— One adrenal from 10-day-old SR-BI knockout (KO) mice or wild-type controls was transplanted under the renal capsule of adrenalectomized C57BL/6 recipient mice. The fasting plasma corticosterone level increased over time in transplanted mice. Corticosterone values in SR-BI KO transplanted mice remained ≈50% lower ( P <0.001) as compared with wild-type transplanted mice, which coincided with adrenocortical lipid depletion. A 6.5-fold higher ( P <0.01) plasma adrenocorticotropic hormone level was present in SR-BI KO transplanted mice reminiscent of primary glucocorticoid insufficiency. On feeding with cholic acid-containing high cholesterol/high fat diet, SR-BI KO transplanted mice exhiBIted a 26% ( P <0.05) reduction in their liver triglyceride level. Hepatic myosin regulatory light chain interacting protein/inducible degrader of the low-density lipoprotein Receptor mRNA expression was 48% ( P <0.01) decreased in adrenal-specific SR-BI KO mice, which was paralleled by a marked decrease (–46%; P <0.01) in proatherogenic very-low-density and low-density lipoprotein levels. Conclusion— Adrenal-specific disruption of SR-BI function induces glucocorticoid insufficiency and lowers plasma very-low-density and low-density lipoprotein levels in atherogenic diet-fed C57BL/6 mice. These findings further highlight the interaction between adrenal high-density lipoprotein-cholesterol uptake by SR-BI, adrenal steroidogenesis, and the regulation of hepatic lipid metabolism.
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native high density lipoproteins inhiBIt platelet activation via Scavenger Receptor BI role of negatively charged phospholipids
Atherosclerosis, 2011Co-Authors: Martin Brodde, Theo J.c. Van Berkel, Miranda Van Eck, Suzanne J A Korporaal, Uwe J F Tietge, Grazyna Herminghaus, Manfred Fobker, Horst Robenek, Beate E Kehrel, Jerzyroch NoferAbstract:Abstract Objectives HIGH-density lipoproteins (HDL) are a negative predictor of platelet-dependent thrombus formation and reduced platelet activation has been observed in vitro in the presence of HDL3, a major HDL fraction. However, mechanisms underlying the anti-thrombotic effects of HDL3 are poorly understood. Scavenger Receptors class B represent possible HDL3 BInding partners on platelets. We here investigated the role of Scavenger Receptor class B type I (SR-BI) and CD36 in mediating inhiBItory effects of native HDL3 on thromBIn-induced platelet activation. Methods and results Rhodamine isothiocyanate-labeled HDL3 bound specifically to platelets and HDL3 BInding was inhiBIted by Scavenger Receptor class B ligands such as phosphatidylserine (PS)- or phosphatidylinositol (PI)-containing liposomes or maleylated albumin (mBSA). By contrast, Scavenger Receptor class A ligands failed to displace HDL3 from platelets. HDL3, PS- and PI-liposomes, and mBSA inhiBIted thromBIn-induced platelet aggregation, fibrinogen BInding, P-selectin expression and moBIlization of intracellular Ca 2+ . In addition, PS- and PI-liposomes emulated HDL3-induced intracellular signaling cascades including diacylglycerol production and protein kinase C activation. The reduction of platelet activation by liposomes was related to their PS or PI content. Moreover, inhiBItory effects of native HDL3 were enhanced after enriching lipoproteins with PS, while PS- and PI-poor HDL2 failed to inhiBIt platelet aggregation and Ca 2+ moBIlization. Both, HDL3 and PS-containing liposomes failed to inhiBIt thromBIn-induced activation of platelets obtained from SR-BI-deficient mice but not CD36-deficient mice. Conclusion We suggest that SR-BI is a functional Receptor for native HDL3 on platelets that generates an inhiBItory signal for platelet activation. The content of negatively charged phospholipids (PS, PI) in HDL may be an important determinant of their anti-thrombotic potential.
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deletion of the high density lipoprotein Receptor Scavenger Receptor BI in mice modulates thrombosis susceptiBIlity and indirectly affects platelet function by elevation of plasma free cholesterol
Arteriosclerosis Thrombosis and Vascular Biology, 2011Co-Authors: Suzanne J A Korporaal, Reeni B Hildebrand, Menno Hoekstra, Theo J.c. Van Berkel, Illiana Meurs, Arnaud D Hauer, Hugo Ten Cate, Domenico Pratico, Janwillem N Akkerman, Johan KuiperAbstract:Objective— Scavenger Receptor BI (SR-BI) is a cell surface Receptor that promotes the selective uptake of cholesteryl esters from high-density lipoprotein (HDL) by the liver. In mice, SR-BI deficiency results in increased plasma HDL cholesterol levels and enhanced susceptiBIlity to atherosclerosis. The aim of this study was to investigate the role of SR-BI deficiency on platelet function. Methods and Results— SR-BI-deficient mice were thrombocytopenic, and their platelets were abnormally large, probably because of an increased cholesterol content. The FeCl 3 acute injury model to study arterial thrombosis susceptiBIlity showed that SR-BI wild-type mice developed total arterial occlusion after 24±2 minutes. In SR-BI-deficient mice, however, the time to occlusion was reduced to 13±1 minutes ( P =0.02). Correspondingly, in SR-BI-deficient mice, platelets circulated in an activated state and showed increased adherence to immoBIlized fibrinogen. In contrast, platelet-specific disruption of SR-BI by bone marrow transplantation in wild-type mice did not alter plasma cholesterol levels or affect platelet count, size, cholesterol content, or reactivity, suggesting that changes in plasma cholesterol levels were responsible for the altered responsiveness of platelets in SR-BI-deficient mice. Conclusion— The function of SR-BI in HDL cholesterol homeostasis and prevention of atherosclerosis is indirectly also essential for maintaining normal platelet function and prevention of thrombosis.
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Scavenger Receptor BI: A multi-purpose player in cholesterol and steroid metabolism
World journal of gastroenterology, 2010Co-Authors: Menno Hoekstra, Theo J.c. Van Berkel, Miranda Van EckAbstract:Scavenger Receptor class B type I (SR-BI) is an important member of the Scavenger Receptor family of integral membrane glycoproteins. This review highlights studies in SR-BI knockout mice, which concern the role of SR-BI in cholesterol and steroid metabolism. SR-BI in hepatocytes is the sole molecule involved in selective uptake of cholesteryl esters from high-density lipoprotein (HDL). SR-BI plays a physiological role in BInding and uptake of native apolipoprotein B (apoB)-containing lipoproteins by hepatocytes, which identifies SR-BI as a multi-purpose player in lipid uptake from the blood circulation into hepatocytes in mice. In adrenocortical cells, SR-BI mediates the selective uptake of HDL-cholesteryl esters, which is efficiently coupled to the synthesis of glucocorticoids (i.e. corticosterone). SR-BI knockout mice suffer from adrenal glucocorticoid insufficiency, which suggests that functional SR-BI protein is necessary for optimal adrenal steroidogenesis in mice. SR-BI in macrophages plays a dual role in cholesterol metabolism as it is able to take up cholesterol associated with HDL and apoB-containing lipoproteins and can possibly facilitate cholesterol efflux to HDL. Absence of SR-BI is associated with thrombocytopenia and altered thrombosis susceptiBIlity, which suggests a novel role for SR-BI in regulating platelet number and function in mice. Transgenic expression of cholesteryl ester transfer protein in humanized SR-BI knockout mice normalizes hepatic delivery of HDL-cholesteryl esters. However, other pathologies associated with SR-BI deficiency, i.e. increased atherosclerosis susceptiBIlity, adrenal glucocorticoid insufficiency, and impaired platelet function are not normalized, which suggests an important role for SR-BI in cholesterol and steroid metabolism in man. In conclusion, generation of SR-BI knockout mice has significantly contributed to our knowledge of the physiological role of SR-BI. Studies using these mice have identified SR-BI as a multi-purpose player in cholesterol and steroid metabolism because it has distinct roles in reverse cholesterol transport, adrenal steroidogenesis, and platelet function.
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apolipoprotein ci inhiBIts Scavenger Receptor BI and increases plasma hdl levels in vivo
Biochemical and Biophysical Research Communications, 2008Co-Authors: Willeke De Haan, Theo J.c. Van Berkel, Ruud Out, Jimmy F P Berbee, Caroline C Van Der Hoogt, Ko Willems Van Dijk, Johannes A Romijn, Wouter J Jukema, Louis M Havekes, Patrick C N RensenAbstract:Apolipoprotein CI (apoCI) has been suggested to influence HDL metabolism by activation of LCAT and inhiBItion of HL and CETP. However, the effect of apoCI on Scavenger Receptor BI (SR-BI)-mediated uptake of HDL-cholesteryl esters (CE), as well as the net effect of apoCI on HDL metabolism in vivo is unknown. Therefore, we evaluated the effect of apoCI on the SR-BI-mediated uptake of HDL-CE in vitro and determined the net effect of apoCI on HDL metabolism in mice. Enrichment of HDL with apoCI dose-dependently decreased the SR-BI-dependent association of [3H]CE-labeled HDL with primary murine hepatocytes, similar to the established SR-BI-inhiBItors apoCIII and oxLDL. ApoCI deficiency in mice gene dose-dependently decreased HDL-cholesterol levels. Adenovirus-mediated expression of human apoCI in mice increased HDL levels at a low dose and increased the HDL particle size at higher doses. We conclude that apoCI is a novel inhiBItor of SR-BI in vitro and increases HDL levels in vivo. © 2008 Elsevier Inc. All rights reserved.
David L Williams - One of the best experts on this subject based on the ideXlab platform.
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cholesterol BInding efflux and a pdz interacting domain of Scavenger Receptor BI mediate hdl initiated signaling
Journal of Clinical Investigation, 2005Co-Authors: Chatchawin Assanasen, Margarita De La Lleramoya, Margery A Connelly, David L Williams, Ivan S Yuhanna, Yves L Marcel, Philip W Shaul, Chieko Mineo, Divya Seetharam, David L SilverAbstract:The BInding of HDL to Scavenger Receptor–BI (SR-BI) mediates cholesterol movement. HDL also induces multiple cellular signals, which in endothelium occur through SR-BI and converge to activate eNOS. To determine the molecular basis of a signaling event induced by HDL, we examined the proximal mechanisms in HDL activation of eNOS. In endothelial cells, HDL and methyl-β-cyclodextrin caused comparable eNOS activation, whereas cholesterol-loaded methyl-β-cyclodextrin had no effect. Phosphatidylcholine-loaded HDL caused greater stimulation than native HDL, and blocking antibody against SR-BI, which prevents cholesterol efflux, prevented eNOS activation. In a reconstitution model in COS-M6 cells, wild-type SR-BI mediated eNOS activation by both HDL and small unilamellar vesicles (SUVs), whereas the SR-BI mutant AVI, which is incapable of efflux to SUV, transmitted signal by only HDL. In addition, eNOS activation by methyl-β-cyclodextrin was SR-BI dependent. Studies of mutant and chimeric class B Scavenger Receptors revealed that the C-terminal cytoplasmic PDZ-interacting domain and the C-terminal transmembrane domains of SR-BI are both necessary for HDL signaling. Furthermore, we demonstrated direct BInding of cholesterol to the C-terminal transmembrane domain using a photoactivated derivative of cholesterol. Thus, HDL signaling requires cholesterol BInding and efflux and C-terminal domains of SR-BI, and SR-BI serves as a cholesterol sensor on the plasma membrane.
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Scavenger Receptor BI: a Scavenger Receptor with a mission to transport high density lipoprotein lipids.
Current opinion in lipidology, 2004Co-Authors: Margery A Connelly, David L WilliamsAbstract:Purpose of reviewThis review will survey recent findings on the cholesterol transport and Scavenger functions of Scavenger Receptor BI. Although Scavenger Receptor BI and CD36 BInd many of the same ligands, these two Receptors have very specific lipid transport functions: CD36 facilitates the uptake
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Scavenger Receptor BI sr BI clustered on microvillar extensions suggests that this plasma membrane domain is a way station for cholesterol trafficking between cells and high density lipoprotein
Molecular Biology of the Cell, 2003Co-Authors: Yinan Peng, Margery A Connelly, Michael C Phillips, Wendy Akmentin, Sissel Lundkatz, David L WilliamsAbstract:Receptor-mediated trafficking of cholesterol between lipoproteins and cells is a fundamental BIological process at the organismal and cellular levels. In contrast to the well-studied pathway of LDL Receptor-mediated endocytosis, little is known about the trafficking of high-density lipoprotein (HDL) cholesterol by the HDL Receptor, Scavenger Receptor BI (SR-BI). SR-BI mediates HDL cholesteryl ester uptake in a process in which HDL lipids are selectively transferred to the cell membrane without the uptake and degradation of the HDL particle. We report here the cell surface locale where the trafficking of HDL cholesterol occurs. Fluorescence confocal microscopy showed SR-BI in patches and small extensions of the cell surface that were distinct from sites of caveolin-1 expression. Electron microscopy showed SR-BI in patches or clusters primarily on microvillar extensions of the plasma membrane. The organization of SR-BI in this manner suggests that this microvillar domain is a way station for cholesterol trafficking between HDL and cells. The types of phospholipids in this domain are unknown, but SR-BI is not strongly associated with classical membrane rafts rich in detergent-resistant saturated phospholipids. We speculate that SR-BI is in a more fluid membrane domain that will favor rapid cholesterol flux between the membrane and HDL.
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apolipoprotein a i is necessary for thein vivo formation of high density lipoprotein competent for Scavenger Receptor BI mediated cholesteryl ester selective uptake
Journal of Biological Chemistry, 2002Co-Authors: Ryan E Temel, Rosemary L Walzem, Carole L Banka, David L WilliamsAbstract:The severe depletion of cholesteryl ester (CE) in steroidogenic cells of apoA-I−/− mice suggests that apolipoprotein (apo) A-I plays a specific role in the high density lipoprotein (HDL) CE-selective uptake process mediated by Scavenger Receptor BI (SR-BI) in vivo. The nature of this role, however, is unclear because a variety of apolipoproteins BInd to SR-BI expressed in transfected cells. In this study the role of apoA-I in SR-BI-mediated HDL CE-selective uptake was tested via analyses of the BIochemical properties ofapoA-I−/− HDL and its interaction with SR-BI on adrenocortical cells, hepatoma cells, and cells expressing a transfected SR-BI. apoA-I−/− HDL are large heterogeneous particles with a core consisting predominantly of CE and a surface enriched in phospholipid, free cholesterol, apoA-II, and apoE. Functional analysis showed apoA-I−/− HDL to BInd to SR-BI with the same or higher affinity as compared withapoA-I+/+ HDL, butapoA-I−/− HDL showed a 2–3-fold decrease in the V max for CE transfer from the HDL particle to adrenal cells. These results indicate that the absence of apoA-I results in HDL particles with a reduced capacity for SR-BI-mediated CE-selective uptake. The reduced V maxillustrates that HDL properties necessary for BInding to SR-BI are distinct from those properties necessary for the transfer of HDL CE from the core of the HDL particle to the plasma membrane. The reduced V max for HDL CE-selective uptake likely contributes to the severe reduction in CE accumulation in steroidogenic cells of apoA-I−/− mice.
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high density lipoprotein phospholipid composition is a major determinant of the BI directional flux and net movement of cellular free cholesterol mediated by Scavenger Receptor BI
Journal of Biological Chemistry, 2000Co-Authors: Patricia G Yancey, Margarita De La Lleramoya, Snehasikta Swarnakar, Pascale Monzo, Seth M Klein, Margery A Connelly, William J Johnson, David L Williams, George H RothblatAbstract:The role of high density lipoprotein (HDL) phospholipid in Scavenger Receptor BI (SR-BI)-mediated free cholesterol flux was examined by manipulating HDL(3) phosphatidylcholine and sphingomyelin content. Both phosphatidylcholine and sphingomyelin enrichment of HDL enhanced the net efflux of cholesterol from SR-BI-expressing COS-7 cells but by two different mechanisms. Phosphatidylcholine enrichment of HDL increased efflux, whereas sphingomyelin enrichment decreased influx of HDL cholesterol. Although similar trends were observed in control (vector-transfected) COS-7 cells, SR-BI overexpression amplified the effects of phosphatidylcholine and sphingomyelin enrichment of HDL 25- and 2.8-fold, respectively. By using both phosphatidylcholine-enriched and phospholipase A(2)-treated HDL to obtain HDL with a graded phosphatidylcholine content, we showed that SR-BI-mediated cholesterol efflux was highly correlated (r(2) = 0.985) with HDL phosphatidylcholine content. The effects of varying HDL phospholipid composition on SR-BI-mediated free cholesterol flux were not correlated with changes in either the K(d) or B(max) values for high affinity BInding to SR-BI. We conclude that SR-BI-mediated free cholesterol flux is highly sensitive to HDL phospholipid composition. Thus, factors that regulate cellular SR-BI expression and the local modification of HDL phospholipid composition will have a large impact on reverse cholesterol transport.
Menno Hoekstra - One of the best experts on this subject based on the ideXlab platform.
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hypercholesterolemia impairs megakaryopoiesis and platelet production in Scavenger Receptor BI knockout mice
Atherosclerosis, 2019Co-Authors: Ambe . Ouweneel, Menno Hoekstra, Suzanne J A Korporaal, Ezra J Van Der Wel, Frank H Schaftenaar, Olga S C Snip, Jasmin Hassan, Miranda Van EckAbstract:Abstract Background and aims Thrombocytopenia in Scavenger Receptor BI (SR-BI) knockout mice is suggested to result from augmented platelet clearance induced by elevated intracellular unesterified cholesterol (UC) levels. We hypothesize that SR-BI deficiency may also influence platelet production at the level of its precursor cell in the bone marrow, the megakaryocyte. Methods In this study, we compared megakaryopoiesis and platelet production in SR-BI knockout and wild-type mice. Results In line with our hypothesis, megakaryocytes from SR-BI knockout mice exhiBIted UC accumulation while no accumulation of UC was detectable in wild-type megakaryocytes. Bone marrow expression of transcription factors involved in megakaryocyte maturation was induced, but megakaryocyte counts were unchanged in bone marrow of SR-BI knockout mice. Interestingly, we did find a striking 62% decrease (p Conclusions In conclusion, the elevation of plasma unesterified cholesterol levels impairs megakaryopoiesis and platelet production in SR-BI knockout mice. Our findings suggest that, in addition to an increased platelet clearance, a decrease in platelet production may also, in part, explain the thrombocytopenic phenotype associated with SR-BI deficiency in mice.
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adrenal specific Scavenger Receptor BI deficiency induces glucocorticoid insufficiency and lowers plasma very low density and low density lipoprotein levels in mice
Arteriosclerosis Thrombosis and Vascular Biology, 2013Co-Authors: Menno Hoekstra, Miranda Van Eck, Ronald J Van Der Sluis, Theo J.c. Van BerkelAbstract:Objective— We determined the physiological consequences of adrenocortical-specific deletion of Scavenger Receptor BI (SR-BI) function in C57BL/6 wild-type mice. Methods and Results— One adrenal from 10-day-old SR-BI knockout (KO) mice or wild-type controls was transplanted under the renal capsule of adrenalectomized C57BL/6 recipient mice. The fasting plasma corticosterone level increased over time in transplanted mice. Corticosterone values in SR-BI KO transplanted mice remained ≈50% lower ( P <0.001) as compared with wild-type transplanted mice, which coincided with adrenocortical lipid depletion. A 6.5-fold higher ( P <0.01) plasma adrenocorticotropic hormone level was present in SR-BI KO transplanted mice reminiscent of primary glucocorticoid insufficiency. On feeding with cholic acid-containing high cholesterol/high fat diet, SR-BI KO transplanted mice exhiBIted a 26% ( P <0.05) reduction in their liver triglyceride level. Hepatic myosin regulatory light chain interacting protein/inducible degrader of the low-density lipoprotein Receptor mRNA expression was 48% ( P <0.01) decreased in adrenal-specific SR-BI KO mice, which was paralleled by a marked decrease (–46%; P <0.01) in proatherogenic very-low-density and low-density lipoprotein levels. Conclusion— Adrenal-specific disruption of SR-BI function induces glucocorticoid insufficiency and lowers plasma very-low-density and low-density lipoprotein levels in atherogenic diet-fed C57BL/6 mice. These findings further highlight the interaction between adrenal high-density lipoprotein-cholesterol uptake by SR-BI, adrenal steroidogenesis, and the regulation of hepatic lipid metabolism.
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hypocholesterolemia foam cell accumulation but no atherosclerosis in mice lacking abc transporter a1 and Scavenger Receptor BI
Atherosclerosis, 2011Co-Authors: Ying Zhao, Carlos L J Vrins, Roelof Ottenhoff, Laura Calpeberdiel, Reeni B Hildebrand, Ronald J. Van Der Sluis, Marieke Pennings, Menno Hoekstra, Kar J Kruijt, Wendy JessupAbstract:Abstract High-density lipoprotein (HDL) mediated reverse cholesterol transport (RCT) is regarded to be crucial for prevention of foam cell formation and atherosclerosis. ABC-transporter A1 (ABCA1) and Scavenger Receptor BI (SR-BI) are involved in the BIogenesis of HDL and the selective delivery of HDL cholesterol to the liver, respectively. In the present study, we phenotypically characterized mice lacking these two proteins essential for HDL metabolism. ABCA1 × SR-BI double knockout (dKO) mice showed severe hypocholesterolemia mainly due to HDL loss, despite a 90% reduction of HDL cholesterol uptake by liver. VLDL production was increased in dKO mice. However, non-HDL cholesterol levels were reduced, probably due to enhanced clearance via LRP1. HepatoBIliary cholesterol transport and fecal sterol excretion were not impaired in dKO mice. In contrast, the macrophage RCT in dKO mice was markedly impaired as compared to WT mice, associated with the accumulation of macrophage foam cells in the lung and Peyer's patches. Strikingly, no atherosclerotic lesion formation was observed in dKO mice. In conclusion, both ABCA1 and SR-BI are essential for maintaining a properly functioning HDL-mediated macrophage RCT, while the potential anti-atherosclerotic functions of ABCA1 and SR-BI are not evident in dKO mice due to the absence of pro-atherogenic lipoproteins.
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genetic variant of the Scavenger Receptor BI in humans
The New England Journal of Medicine, 2011Co-Authors: Menno Vergeer, Menno Hoekstra, Ruud Out, Suzanne J A Korporaal, Remco Franssen, Illiana Meurs, Kees G Hovingh, Jeroen A Sierts, Geesje M Dallingathie, Mahdi M MotazackerAbstract:Background In mice, the Scavenger Receptor class B type I (SR-BI) is essential for the delivery of high-density lipoprotein (HDL) cholesterol to the liver and steroidogenic organs. Paradoxically, elevated HDL cholesterol levels are associated with increased atherosclerosis in SR-BI-knockout mice. It is unclear what role SR-BI plays in human metabolism. Methods We sequenced the gene encoding SR-BI in persons with elevated HDL cholesterol levels and identified a family with a new missense mutation (P297S). The functional effects of the P297S mutation on HDL BInding, cellular cholesterol uptake and efflux, atherosclerosis, platelet function, and adrenal function were studied. Results Cholesterol uptake from HDL by primary murine hepatocytes that expressed mutant SR-BI was reduced to half of that of hepatocytes expressing wild-type SR-BI. Carriers of the P297S mutation had increased HDL cholesterol levels (70.4 mg per deciliter [1.8 mmol per liter], vs. 53.4 mg per deciliter [1.4 mmol per liter] in noncarriers; P Conclusions We identified a family with a functional mutation in SR-BI. The mutation carriers had increased HDL cholesterol levels and a reduction in cholesterol efflux from macrophages but no significant increase in atherosclerosis. Reduced SR-BI function was associated with altered platelet function and decreased adrenal steroidogenesis. (Funded by the European Community and others.).
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deletion of the high density lipoprotein Receptor Scavenger Receptor BI in mice modulates thrombosis susceptiBIlity and indirectly affects platelet function by elevation of plasma free cholesterol
Arteriosclerosis Thrombosis and Vascular Biology, 2011Co-Authors: Suzanne J A Korporaal, Reeni B Hildebrand, Menno Hoekstra, Theo J.c. Van Berkel, Illiana Meurs, Arnaud D Hauer, Hugo Ten Cate, Domenico Pratico, Janwillem N Akkerman, Johan KuiperAbstract:Objective— Scavenger Receptor BI (SR-BI) is a cell surface Receptor that promotes the selective uptake of cholesteryl esters from high-density lipoprotein (HDL) by the liver. In mice, SR-BI deficiency results in increased plasma HDL cholesterol levels and enhanced susceptiBIlity to atherosclerosis. The aim of this study was to investigate the role of SR-BI deficiency on platelet function. Methods and Results— SR-BI-deficient mice were thrombocytopenic, and their platelets were abnormally large, probably because of an increased cholesterol content. The FeCl 3 acute injury model to study arterial thrombosis susceptiBIlity showed that SR-BI wild-type mice developed total arterial occlusion after 24±2 minutes. In SR-BI-deficient mice, however, the time to occlusion was reduced to 13±1 minutes ( P =0.02). Correspondingly, in SR-BI-deficient mice, platelets circulated in an activated state and showed increased adherence to immoBIlized fibrinogen. In contrast, platelet-specific disruption of SR-BI by bone marrow transplantation in wild-type mice did not alter plasma cholesterol levels or affect platelet count, size, cholesterol content, or reactivity, suggesting that changes in plasma cholesterol levels were responsible for the altered responsiveness of platelets in SR-BI-deficient mice. Conclusion— The function of SR-BI in HDL cholesterol homeostasis and prevention of atherosclerosis is indirectly also essential for maintaining normal platelet function and prevention of thrombosis.
Miranda Van Eck - One of the best experts on this subject based on the ideXlab platform.
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hypercholesterolemia impairs megakaryopoiesis and platelet production in Scavenger Receptor BI knockout mice
Atherosclerosis, 2019Co-Authors: Ambe . Ouweneel, Menno Hoekstra, Suzanne J A Korporaal, Ezra J Van Der Wel, Frank H Schaftenaar, Olga S C Snip, Jasmin Hassan, Miranda Van EckAbstract:Abstract Background and aims Thrombocytopenia in Scavenger Receptor BI (SR-BI) knockout mice is suggested to result from augmented platelet clearance induced by elevated intracellular unesterified cholesterol (UC) levels. We hypothesize that SR-BI deficiency may also influence platelet production at the level of its precursor cell in the bone marrow, the megakaryocyte. Methods In this study, we compared megakaryopoiesis and platelet production in SR-BI knockout and wild-type mice. Results In line with our hypothesis, megakaryocytes from SR-BI knockout mice exhiBIted UC accumulation while no accumulation of UC was detectable in wild-type megakaryocytes. Bone marrow expression of transcription factors involved in megakaryocyte maturation was induced, but megakaryocyte counts were unchanged in bone marrow of SR-BI knockout mice. Interestingly, we did find a striking 62% decrease (p Conclusions In conclusion, the elevation of plasma unesterified cholesterol levels impairs megakaryopoiesis and platelet production in SR-BI knockout mice. Our findings suggest that, in addition to an increased platelet clearance, a decrease in platelet production may also, in part, explain the thrombocytopenic phenotype associated with SR-BI deficiency in mice.
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adrenal specific Scavenger Receptor BI deficiency induces glucocorticoid insufficiency and lowers plasma very low density and low density lipoprotein levels in mice
Arteriosclerosis Thrombosis and Vascular Biology, 2013Co-Authors: Menno Hoekstra, Miranda Van Eck, Ronald J Van Der Sluis, Theo J.c. Van BerkelAbstract:Objective— We determined the physiological consequences of adrenocortical-specific deletion of Scavenger Receptor BI (SR-BI) function in C57BL/6 wild-type mice. Methods and Results— One adrenal from 10-day-old SR-BI knockout (KO) mice or wild-type controls was transplanted under the renal capsule of adrenalectomized C57BL/6 recipient mice. The fasting plasma corticosterone level increased over time in transplanted mice. Corticosterone values in SR-BI KO transplanted mice remained ≈50% lower ( P <0.001) as compared with wild-type transplanted mice, which coincided with adrenocortical lipid depletion. A 6.5-fold higher ( P <0.01) plasma adrenocorticotropic hormone level was present in SR-BI KO transplanted mice reminiscent of primary glucocorticoid insufficiency. On feeding with cholic acid-containing high cholesterol/high fat diet, SR-BI KO transplanted mice exhiBIted a 26% ( P <0.05) reduction in their liver triglyceride level. Hepatic myosin regulatory light chain interacting protein/inducible degrader of the low-density lipoprotein Receptor mRNA expression was 48% ( P <0.01) decreased in adrenal-specific SR-BI KO mice, which was paralleled by a marked decrease (–46%; P <0.01) in proatherogenic very-low-density and low-density lipoprotein levels. Conclusion— Adrenal-specific disruption of SR-BI function induces glucocorticoid insufficiency and lowers plasma very-low-density and low-density lipoprotein levels in atherogenic diet-fed C57BL/6 mice. These findings further highlight the interaction between adrenal high-density lipoprotein-cholesterol uptake by SR-BI, adrenal steroidogenesis, and the regulation of hepatic lipid metabolism.
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native high density lipoproteins inhiBIt platelet activation via Scavenger Receptor BI role of negatively charged phospholipids
Atherosclerosis, 2011Co-Authors: Martin Brodde, Theo J.c. Van Berkel, Miranda Van Eck, Suzanne J A Korporaal, Uwe J F Tietge, Grazyna Herminghaus, Manfred Fobker, Horst Robenek, Beate E Kehrel, Jerzyroch NoferAbstract:Abstract Objectives HIGH-density lipoproteins (HDL) are a negative predictor of platelet-dependent thrombus formation and reduced platelet activation has been observed in vitro in the presence of HDL3, a major HDL fraction. However, mechanisms underlying the anti-thrombotic effects of HDL3 are poorly understood. Scavenger Receptors class B represent possible HDL3 BInding partners on platelets. We here investigated the role of Scavenger Receptor class B type I (SR-BI) and CD36 in mediating inhiBItory effects of native HDL3 on thromBIn-induced platelet activation. Methods and results Rhodamine isothiocyanate-labeled HDL3 bound specifically to platelets and HDL3 BInding was inhiBIted by Scavenger Receptor class B ligands such as phosphatidylserine (PS)- or phosphatidylinositol (PI)-containing liposomes or maleylated albumin (mBSA). By contrast, Scavenger Receptor class A ligands failed to displace HDL3 from platelets. HDL3, PS- and PI-liposomes, and mBSA inhiBIted thromBIn-induced platelet aggregation, fibrinogen BInding, P-selectin expression and moBIlization of intracellular Ca 2+ . In addition, PS- and PI-liposomes emulated HDL3-induced intracellular signaling cascades including diacylglycerol production and protein kinase C activation. The reduction of platelet activation by liposomes was related to their PS or PI content. Moreover, inhiBItory effects of native HDL3 were enhanced after enriching lipoproteins with PS, while PS- and PI-poor HDL2 failed to inhiBIt platelet aggregation and Ca 2+ moBIlization. Both, HDL3 and PS-containing liposomes failed to inhiBIt thromBIn-induced activation of platelets obtained from SR-BI-deficient mice but not CD36-deficient mice. Conclusion We suggest that SR-BI is a functional Receptor for native HDL3 on platelets that generates an inhiBItory signal for platelet activation. The content of negatively charged phospholipids (PS, PI) in HDL may be an important determinant of their anti-thrombotic potential.
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Scavenger Receptor BI: A multi-purpose player in cholesterol and steroid metabolism
World journal of gastroenterology, 2010Co-Authors: Menno Hoekstra, Theo J.c. Van Berkel, Miranda Van EckAbstract:Scavenger Receptor class B type I (SR-BI) is an important member of the Scavenger Receptor family of integral membrane glycoproteins. This review highlights studies in SR-BI knockout mice, which concern the role of SR-BI in cholesterol and steroid metabolism. SR-BI in hepatocytes is the sole molecule involved in selective uptake of cholesteryl esters from high-density lipoprotein (HDL). SR-BI plays a physiological role in BInding and uptake of native apolipoprotein B (apoB)-containing lipoproteins by hepatocytes, which identifies SR-BI as a multi-purpose player in lipid uptake from the blood circulation into hepatocytes in mice. In adrenocortical cells, SR-BI mediates the selective uptake of HDL-cholesteryl esters, which is efficiently coupled to the synthesis of glucocorticoids (i.e. corticosterone). SR-BI knockout mice suffer from adrenal glucocorticoid insufficiency, which suggests that functional SR-BI protein is necessary for optimal adrenal steroidogenesis in mice. SR-BI in macrophages plays a dual role in cholesterol metabolism as it is able to take up cholesterol associated with HDL and apoB-containing lipoproteins and can possibly facilitate cholesterol efflux to HDL. Absence of SR-BI is associated with thrombocytopenia and altered thrombosis susceptiBIlity, which suggests a novel role for SR-BI in regulating platelet number and function in mice. Transgenic expression of cholesteryl ester transfer protein in humanized SR-BI knockout mice normalizes hepatic delivery of HDL-cholesteryl esters. However, other pathologies associated with SR-BI deficiency, i.e. increased atherosclerosis susceptiBIlity, adrenal glucocorticoid insufficiency, and impaired platelet function are not normalized, which suggests an important role for SR-BI in cholesterol and steroid metabolism in man. In conclusion, generation of SR-BI knockout mice has significantly contributed to our knowledge of the physiological role of SR-BI. Studies using these mice have identified SR-BI as a multi-purpose player in cholesterol and steroid metabolism because it has distinct roles in reverse cholesterol transport, adrenal steroidogenesis, and platelet function.
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Scavenger Receptor BI facilitates the metabolism of vldl lipoproteins in vivo
Journal of Lipid Research, 2008Co-Authors: Miranda Van Eck, Reeni B Hildebrand, Menno Hoekstra, Kar J Kruijt, Ruud Out, Sophie I T Bos, Theo J.c. Van BerkelAbstract:Scavenger Receptor class B type I (SR-BI) functions as an HDL Receptor that promotes the selective uptake of cholesteryl esters (CEs). The physiological role of SR-BI in VLDL metabolism, however, is largely unknown. SR-BI deficiency resulted in elevated VLDL cholesterol levels, both on chow diet and upon challenge with high-cholesterol diets. To specifically elucidate the role of SR-BI in VLDL metabolism, the plasma clearance and hepatic uptake of 125I-β-VLDL were studied in SR-BI+/+ and SR-BI−/− mice. At 20 min after injection, 66 ± 2% of the injected dose was taken up by the liver in SR-BI+/+ mice, as compared with only 22 ± 4% (P = 0.0007) in SR-BI−/− mice. In vitro studies established that the Bmax of 125I-β-VLDL BInding was reduced from 469 ± 30 ng/mg in SR-BI+/+ hepatocytes to 305 ± 20 ng/mg (P = 0.01) in SR-BI−/− hepatocytes. Both in vivo and in vitro, limited to no selective uptake of CEs from β-VLDL was found. Interestingly, HDL effectively competed for the association of β-VLDL in the presence as well as in the absence of SR-BI, indicating a second common recognition site. In conclusion, SR-BI plays an important physiological role in the metabolism of VLDL (remnants).
Alan R Tall - One of the best experts on this subject based on the ideXlab platform.
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Scavenger Receptor BI inhiBIts atp BInding cassette transporter 1 mediated cholesterol efflux in macrophages
Journal of Biological Chemistry, 2000Co-Authors: Wengen Chen, David L Silver, Jonathan D Smith, Alan R TallAbstract:Scavenger Receptor BI (SR-BI) facilitates the efflux of cellular cholesterol to plasma high density lipoprotein (HDL). Recently, the ATP-BInding cassette transporter 1 (ABC1) was identified as a key mediator of cholesterol efflux to apolipoproteins and HDL. The goal of the present study was to determine a possible interaction between the SR-BI and ABC1 cholesterol efflux pathways in macrophages. Free cholesterol efflux to HDL was increased (∼2.2-fold) in SR-BI transfected RAW macrophages in association with increased SR-BI protein levels. Treatment of macrophages with 8-bromo-cAMP (cAMP) resulted in a 4.1-fold increase in ABC1 mRNA level and also increased cholesterol efflux to HDL (2.2-fold) and apoA-I (5.5-fold). However, in SR-BI transfected RAW cells, cAMP treatment produced a much smaller increment in cholesterol efflux to HDL (1.1-fold) or apoA-I (3.3-fold) compared with control cells. In macrophages loaded with cholesterol by acetyl-LDL treatment, SR-BI overexpression did not increase cholesterol efflux to HDL but did inhiBIt cAMP-mediated cholesterol efflux to apoA-I or HDL. SR-BI neutralizing antibody led to a dose- and time-dependent increase of cAMP-mediated cholesterol efflux in both SR-BI transfected and control cells, indicating that SR-BI inhiBIts ABC1-mediated cholesterol efflux even at low SR-BI expression level. Transfection of a murine ABC1 cDNA into 293 cells led to a 2.3-fold increase of cholesterol efflux to apoA-I, whereas co-transfection of SR-BI with ABC1 blocked this increase in cholesterol efflux. SR-BI and ABC1 appear to have distinct and competing roles in mediating cholesterol flux between HDL and macrophages. In nonpolarized cells, SR-BI promotes the reuptake of cholesterol actively effluxed by ABC1, creating a futile cycle.
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hepatic Scavenger Receptor BI promotes rapid clearance of high density lipoprotein free cholesterol and its transport into BIle
Journal of Biological Chemistry, 1999Co-Authors: Nan Wang, Rajasekhar Ramakrishnan, Ephraim Sehayek, Dennis Huszar, Jan L Breslow, Alan R TallAbstract:The clearance of free cholesterol from plasma lipoproteins by tissues is of major quantitative importance, but it is not known whether this is passive or Receptor-mediated. Based on our finding that Scavenger Receptor BI (SR-BI) promotes free cholesterol (FC) exchange between high density lipoprotein (HDL) and cells, we tested whether SR-BI would effect FC movement in vivo using [14C]FC- and [3H]cholesteryl ester (CE)-labeled HDL in mice with increased (SR-BI transgenic (Tg)) or decreased (SR-BI attenuated (att)) hepatic SR-BI expression. The initial clearance of HDL FC was increased in SR-BI Tg mice by 72% and decreased in SR-BI att mice by 53%, but was unchanged in apoA-I knockout mice compared with wild-type mice. Transfer of FC to non-HDL and esterification of FC were minor and could not explain differences. The hepatic uptake of FC was increased in SR-BI Tg mice by 34% and decreased in SR-BI att mice by 22%. CE clearance and uptake gave similar results, but with much slower rates. The uptake of HDL FC and CE by SR-BI Tg primary hepatocytes was increased by 2.2- and 2.6-fold (1-h incubation), respectively, compared with control hepatocytes. In SR-BI Tg mice, the initial BIliary secretion of [14C]FC was markedly increased, whereas increased [3H]FC appeared after a slight delay. Thus, in the mouse, a major portion of the clearance of HDL FC from plasma is mediated by SR-BI.
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regulation of adrenal Scavenger Receptor BI expression by acth and cellular cholesterol pools
Journal of Lipid Research, 1999Co-Authors: Yu Sun, Nan Wang, Alan R TallAbstract:Scavenger Receptor BI (SR-BI) mediates selective uptake of high density lipoprotein (HDL) cholesteryl ester in the liver and adrenal gland. Adrenal SR-BI is increased both in adrenocorticotropic hormone (ACTH)-treated mice and also in apolipoprotein A-I knock-out (apoA-I0) mice which have depleted adrenal cholesterol stores. The goal of the present study was to determine whether adrenal cholesterol stores and ACTH have independent effects on SR-BI ex- pression in adrenal gland. Adrenal SR-BI levels were 5-fold higher in apoA-I0 than wild-type mice when killed under low stress condition, and plasma ACTH levels were similar in both strains. After male apoA-I0 or wild-type mice were treated with dexamethasone to suppress ACTH release, adrenal SR- BI protein levels were decreased in both groups but re- mained 13-fold higher in apoA-I0 than in wild-type mice. By contrast, uncontrolled stress or supplemental ACTH treat- ment increased SR-BI levels but narrowed the difference in SR-BI expression between apoA-I0 and wild-type. Choles- terol depletion by b -cyclodextrin in cultured Y1-BS1 adre- nal cells also led to a rapid 2- to 3-fold increase in SR-BI mRNA and protein levels, in association with a significant depletion of cellular free cholesterol. These results indi- cate that depletion of adrenal cholesterol stores can act in- dependently from ACTH to increase SR-BI expression, but in vivo this effect is diminished under high ACTH condi- tions. Both stimuli may increase selective uptake via in- creased SR-BI as a means of replenishing cholesterol stores for steroid hormone synthesis. —Sun, Y., N. Wang, and A. R. Tall. Regulation of adrenal Scavenger Receptor-BI expres- sion by ACTH and cellular cholesterol pools. J. Lipid Res. 1999. 40: 1799-1805.
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regulation of adrenal Scavenger Receptor BI expression by acth and cellular cholesterol pools
Journal of Lipid Research, 1999Co-Authors: Yu Sun, Nan Wang, Alan R TallAbstract:Scavenger Receptor BI (SR-BI) mediates selective uptake of high density lipoprotein (HDL) cholesteryl ester in the liver and adrenal gland. Adrenal SR-BI is increased both in adrenocorticotropic hormone (ACTH)-treated mice and also in apolipoprotein A-I knock-out (apoA-I0) mice which have depleted adrenal cholesterol stores. The goal of the present study was to determine whether adrenal cholesterol stores and ACTH have independent effects on SR-BI expression in adrenal gland. Adrenal SR-BI levels were 5-fold higher in apoA-I0 than wild-type mice when killed under low stress condition, and plasma ACTH levels were similar in both strains. After male apoA-I0 or wild-type mice were treated with dexamethasone to suppress ACTH release, adrenal SR-BI protein levels were decreased in both groups but remained 13-fold higher in apoA-I0 than in wild-type mice. By contrast, uncontrolled stress or supplemental ACTH treatment increased SR-BI levels but narrowed the difference in SR-BI expression between apoA-I0 and wild-type. Cholesterol depletion by beta-cyclodextrin in cultured Y1-BS1 adrenal cells also led to a rapid 2- to 3-fold increase in SR-BI mRNA and protein levels, in association with a significant depletion of cellular free cholesterol. These results indicate that depletion of adrenal cholesterol stores can act independently from ACTH to increase SR-BI expression, but in vivo this effect is diminished under high ACTH conditions. Both stimuli may increase selective uptake via increased SR-BI as a means of replenishing cholesterol stores for steroid hormone synthesis.
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decreased atherosclerosis in heterozygous low density lipoprotein Receptor deficient mice expressing the Scavenger Receptor BI transgene
Journal of Biological Chemistry, 1999Co-Authors: Takeshi Arai, Nan Wang, Mikhail Bezouevski, Carrie L Welch, Alan R TallAbstract:Scavenger Receptor type B class I (SR-BI), initially identified as a Receptor that recognizes low density lipoprotein (LDL), was recently shown to mediate the selective uptake of high density lipoprotein (HDL) cholesteryl esters in liver and steroidogenic tissues. To evaluate effects on atherosclerosis, transgenic mice with liver-specific overexpression of SR-BI (SR-BI Tg mice) have been crossed onto LDL Receptor-deficient backgrounds. To induce atherosclerosis in a setting of moderate hypercholesterolemia, heterozygous LDL Receptor-deficient mice (LDLR1) were fed a high fat/cholesterol/BIle salt diet, and homozygous LDL Receptor knock-outs (LDLR0) were fed a high fat/cholesterol diet. LDLR1/SR-BI Tg mice showed decreases in VLDL, LDL, and HDL cholesterol and a significant 80% decrease in mean lesion area in the aortic root compared with LDLR1 mice (female LDLR1 74, 120 μm2 versus LDLR1/SR-BI Tg 12, 667 μm2; male 25, 747 μm2 versus 5, 448 μm2, respectively). LDLR0/SR-BI Tg mice showed decreased LDL and HDL cholesterol but increased VLDL cholesterol and no significant difference in extent of atherosclerosis compared with LDLR0 mice. ComBIned data analysis showed a strong correlation between atherosclerotic lesion area and the VLDL+LDL cholesterol level but no correlation with HDL level. These studies demonstrate a strong anti-atherogenic potential of hepatic SR-BI overexpression. In mice with marked overexpression of SR-BI, the protective effect appears to be primarily related to the lowering of VLDL and LDL cholesterol levels.
