Scavenger Receptor Class B Type I Mediates the Selective Uptake of High-Density Lipoprotein–Associated Cholesteryl Ester by the Liver in Mice

Brundert, May; Ewert, Anne; Heeren, Joerg; Behrendt, B.; Ramakrishnan, Rajasekhar; Greten, H.; Merkel, Martin; Rinninger, Franz

doi:10.1161/01.atv.0000149381.16166.c6

Cited by 100 publications

(115 citation statements)

References 25 publications

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“…Abundant data have indicated that, in rodents, SR-B1 is a critical regulator of HDL metabolism [39][40][41] . Presently, the roles of dietary fat in modulating the expression of SR-B1 are not clear.…”

Section: Discussionmentioning

confidence: 99%

High Dietary n-6/n-3 PUFA Ratio Promotes HDL Cholesterol Level, but does not Suppress Atherogenesis in Apolipoprotein E-Null Mice 1

Zhang

Geng

Xiao

et al. 2009

JAT

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Aim: Dietary fatty acids affect atherogenesis, which was presumed to be partly related to HDL cholesterol (HDL-C) metabolism. The major aim of the work was to analyze various ratios of n-6 / n-3 PUFA diets on HDL-C metabolism in apolipoprotein E-null (apoE / ) mice, which have similar symptoms to human type familial hyperlipoproteinemia. Methods: Two-month-old male apoE / mice were fed four types of n-6 / n-3 PUFA diet (group 1, 1.28; group 2, 5.03; group 3, 9.98 and group 4, 68.26) and control diet, respectively, for 6 weeks. With respect to serum apolipoprotein (apo) A-concentration, lecithin-cholesterol acyltransferase (LCAT) activity and mRNA abundance of genes involved in HDL-C metabolism in the liver were analyzed. Results: Group 4 diet significantly increased the plasma HDL-C and apoA-concentrations compared with other groups. LCAT activity in serum increased with decreased ratios of n-6 / n-3 PUFA. As the dietary ratio of n-6 / n-3 fatty acids increased, so did mRNA levels of hepatic apoA-, scavenger receptor B class-1 (SR-B1), LCAT, ATP binding cassette transporter A1 (ABCA1), ABCG1 and liver X receptor alpha (LXR ). ApoA-mRNA level, however, had a tendency to fall. Group 4 diet increased apoA-and ABCA1 and decreased apoA-transcriptional levels, whereas group 1 diet decreased mRNA levels of apoA-, LCAT, SR-B1 and ABCG1. Conclusion: Our data indicated that a high ratio of n-6 / n-3 PUFA increased the serum HDL-C level, but did not effectively suppress atherogenesis in apoE / mice. The elevated HDL-C level is possibly due to up-regulated hepatic apoA-and ABCA1 with suppression of apoA-expression.

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Section: Discussionmentioning

confidence: 99%

High Dietary n-6/n-3 PUFA Ratio Promotes HDL Cholesterol Level, but does not Suppress Atherogenesis in Apolipoprotein E-Null Mice 1

Zhang

Geng

Xiao

et al. 2009

JAT

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“…Caveolae, cytosol, and internal membranes were isolated using Opti-Prep method as described previously ( 7,8 ). This method generates a highly purifi ed fraction of caveolae that is enriched in caveolin-1 and free of bulk plasma membrane markers.…”

Section: Isolation Of Caveolaementioning

confidence: 99%

C323 of SR-BI is required for SR-BI-mediated HDL binding and cholesteryl ester uptake

Guo

Chen

Song

et al. 2011

Journal of Lipid Research

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This article is available online at http://www.jlr.org from HDL into hepatocytes and subsequently secretes cholesterol from bile. SR-BI-mediated cholesteryl ester uptake is also required for steroidogenesis, in which SR-BI uptakes cholesteryl ester from HDL into endocrine tissues for steroid synthesis ( 3-7 ). The importance of SR-BI-mediated cholesterol transport has been established in mouse models. Mice defi cient in SR-BI have a 2-fold increase in total cholesterol concentration and a 3-fold increase in free cholesterol concentration in circulation, and they develop cardiovascular diseases ( 8-13 ). Mice overexpressing SR-BI have lower plasma cholesterol levels ( 14-17 ) and are protected against the development of atherosclerosis ( 11,18 ). A recent report showed that a family with functional mutation in SR-BI has elevated plasma HDL and changes in cholesterol metabolism in macrophages and platelets, indicating a role of SR-BI in humans ( 19 ). In addition to modulating HDL metabolism, recent studies revealed that SR-BI is a multifunctional protein. It activates eNOS in endothelial cells in the presence of HDL ( 20-23 ), induces apoptosis in the absence of HDL/eNOS ( 24 ), protects against nitric oxide (NO)-induced oxidative damage ( 25 ), and prevents endotoxic and septic animal death ( 25-27 ).SR-BI facilitates intracellular uptake of HDL cholesteryl esters in a two-step process involving binding of HDL through its extracellular domain and transferring cholesteryl ester from HDL into cells. The importance of extracellular domain of SR-BI in cholesteryl ester uptake has been explored by the use of chimeric receptors ( 28 ), by insertion of epitope tags into various regions of the domain of SR-BI ( 29 ), by blocking antibody against the extracellular domain, and by mutations ( 30, 31 ). However, SR-BI has a large extracellular domain that contains 403 amino acid residues, and the HDL binding site remains to be determined. Identifying the HDL binding site and understanding the regulation of SR-BI-mediated cholesterol Abstract Scavenger receptor BI (SR-BI) is an HDL receptor. It binds HDL and mediates the uptake of cholesteryl ester from HDL. Early studies have pointed out that the extracellular domain of SR-BI is critical for SR-BI-mediated cholesteryl ester uptake. However, the extracellular loop of SR-BI is large: it contains 403 amino acids. The HDL binding site and the modulation of SR-BI-mediated cholesteryl ester uptake remain to be identifi ed. In this study, using C323G mutant SR-BI, we showed that C323G mutant SR-BI lost its HDL binding and cholesteryl ester uptake activity, indicating that the highly conserved C323 is required for SR-BI-mediated HDL binding and cholesteryl ester uptake. Using a blocking antibody against C323 region, we demonstrated that C323 is directly involved in HDL binding and likely an HDL binding site. Using C323G mutant transgenic mouse model, we further demonstrated that C323 of SR-BI is required for regulating plasma cholesterol levels in vivo.Using redox reagents, we show...

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“…In SR-BI-deficient mice, HDL selective CE uptake by the liver decreases by more than 90% but HDL holoparticle uptake is unchanged, suggesting that holoparticle uptake does not involve SR-BI. 2,3 A likely candidate mechanism mediating HDL holoparticle uptake in the absence of SR-BI is the cell-surface complex related to mitochondrial F 1 -adenosine triphosphatase (ATPase), namely ecto-F 1 -ATPase. 4 When HDL binds to apolipoprotein A-I (apoA-I), this enzyme generates extracellular adenosine diphosphate (ADP) which then specifically activates the P2Y 13 receptor which is a Gprotein-coupled receptor.…”

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confidence: 99%

P2Y13 receptor is critical for reverse cholesterol transport

et al. 2010

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A major atheroprotective functionality of high-density lipoproteins (HDLs) is to promote ''reverse cholesterol transport'' (RCT). In this process, HDLs mediate the efflux and transport of cholesterol from peripheral cells and its subsequent transport to the liver for further metabolism and biliary excretion. We have previously demonstrated in cultured hepatocytes that P2Y 13 (purinergic receptor P2Y, G protein-coupled, 13) activation is essential for HDL uptake but the potential of P2Y 13 as a target to promote RCT has not been documented. Here, we show that P2Y 13 -deficient mice exhibited a decrease in hepatic HDL cholesterol uptake, hepatic cholesterol content, and biliary cholesterol output, although their plasma HDL and other lipid levels were normal. These changes translated into a substantial decrease in the rate of macrophage-to-feces RCT. Therefore, hallmark features of RCT are impaired in P2Y 13 -deficient mice. Furthermore, cangrelor, a partial agonist of P2Y 13 , stimulated hepatic HDL uptake and biliary lipid secretions in normal mice and in mice with a targeted deletion of scavenger receptor class B type I (SR-BI) in liver (hypomSR-BIknockout liver ) but had no effect in P2Y 13 knockout mice, which indicate that P2Y 13 -mediated HDL uptake pathway is independent of SR-BI-mediated HDL selective cholesteryl ester uptake. Conclusion: These results establish P2Y 13 as an attractive novel target for modulating RCT and support the emerging view that steady-state plasma HDL levels do not necessarily reflect the capacity of HDL to promote RCT.

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Scavenger Receptor Class B Type I Mediates the Selective Uptake of High-Density Lipoprotein–Associated Cholesteryl Ester by the Liver in Mice

Cited by 100 publications

References 25 publications

High Dietary n-6/n-3 PUFA Ratio Promotes HDL Cholesterol Level, but does not Suppress Atherogenesis in Apolipoprotein E-Null Mice 1

High Dietary n-6/n-3 PUFA Ratio Promotes HDL Cholesterol Level, but does not Suppress Atherogenesis in Apolipoprotein E-Null Mice 1

C323 of SR-BI is required for SR-BI-mediated HDL binding and cholesteryl ester uptake

P2Y13 receptor is critical for reverse cholesterol transport

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