Secretory phospholipase A2 increases SR-BI-mediated selective uptake from HDL but not biliary cholesterol secretion

Tietge, Uwe J. F.; Nijstad, Niels; Havinga, Rick; Baller, Jfw; Sluijs, Fjodor H. van der; Bloks, Vincent W.; Gautier, Thomas; Kuipers, Folkert

doi:10.1194/jlr.m700276-jlr200

Cited by 22 publications

(35 citation statements)

References 40 publications

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“…Consistent with our current study, the expression of the Srebp2 target genes Ldlr as well as HMGCoA reductase was also decreased. 27 Taken together, these data suggest that cholesterol derived from HDL and entering the liver via SR-BI is partitioned into compartments accessible toward Srebp2 but not toward Lxr sensing. Identification of the nature of these compartments will be the subject of future work.…”

Section: Discussionmentioning

confidence: 77%

“…However, the data of our current study are in line with previous results in a model with increased influx via SR-BI into the liver in the face of unchanged hepatic SR-BI mRNA and protein expression levels. 27 In this model, an increase in HDL cholesterol catabolism by overexpression of sPLA 2 resulted in increased hepatic cholesterol content, but without any change in the expression of Lxr target genes. Consistent with our current study, the expression of the Srebp2 target genes Ldlr as well as HMGCoA reductase was also decreased.…”

Section: Discussionmentioning

confidence: 84%

“…Previous studies from our group in transgenic mice indicated that modifying the main SR-BI ligand, HDL, through the action of secretory phospholipase A 2 (sPLA 2 ) results in a significant increase in the mass flux of cholesterol through SR-BI into the liver and subsequently an increased hepatic cholesterol content in the face of unchanged hepatic SR-BI expression and localization. 27 Under these conditions, biliary cholesterol secretion remains unchanged in sPLA 2 transgenic mice. However, if the hepatic expression level of SR-BI is increased by means of a recombinant adenovirus, biliary cholesterol secretion increases in transgenic mice even beyond levels observed in C57BL/6J controls (Supporting Fig.…”

Section: Discussionmentioning

confidence: 99%

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Scavenger receptor class B type I mediates biliary cholesterol secretion independent of ATP-binding cassette transporter g5/g8 in mice

et al. 2009

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Scavenger receptor class B type I (SR-BI) mediates selective uptake of cholesterol from highdensity lipoprotein (HDL) particles by the liver and influences biliary cholesterol secretion. However, it is not clear, if this effect is direct or indirect. The aim of this study was to determine the impact of SR-BI on biliary cholesterol secretion, especially in a functional context with ATP-binding cassette transporter g5 (Abcg5)/Abcg8 and Abcb4. SR-BI was overexpressed by means of adenovirus (AdSR-BI) in livers of wild-type, liver X receptor-null (Lxr ؊/؊ ), Abcg5 ؊/؊ , and Abcb4 ؊/؊ mice. Consistent with previous reports, AdSR-BI decreased plasma HDL cholesterol levels in all models (P < 0.001). Hepatic cholesterol content increased (at least P < 0.05), whereas expression of sterol regulatory element binding protein 2 target genes was decreased (at least P < 0.05,) and established Lxr target genes were unaltered. Biliary cholesterol secretion was increased by AdSR-BI in wild-type as well as in Lxr ؊/؊ and Abcg5 ؊/؊ mice, and considerably less in Abcb4 ؊/؊ mice (each P < 0.001), independent of bile acid and phospholipid secretion. T he scavenger receptor class B type I (SR-BI) has been characterized as a receptor that mediates cholesterol transport across membranes. 1,2 In nonpolarized cells, namely macrophages and the hepatoma cell line Fu5AH, SR-BI expression either results in selective uptake of cholesterol, mainly from high-density lipoprotein (HDL), or in cholesterol efflux toward suitable acceptors. [3][4][5][6] In hepatocytes, which is a highly polarized cell type, SR-BI is the main receptor responsible for selective uptake of cholesterol from plasma HDL. 7 Consequently, hepatic overexpression of SR-BI results in decreased plasma HDL cholesterol levels, 8-10 whereas SR-BI knockout mice have increased plasma HDL cholesterol. 11,12 Interestingly, hepatocyte SR-BI appears to accelerate reverse cholesterol transport in vivo in the face of decreased plasma HDL cholesterol levels, 13 which is in line with studies demonstrating that hepatic SR-BI expression protects against atherosclerosis development in mouse models. 14,15 Hepatic SR-BI expression is also linked to biliary cholesterol

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Section: Discussionmentioning

confidence: 77%

Section: Discussionmentioning

confidence: 84%

Section: Discussionmentioning

confidence: 99%

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Scavenger receptor class B type I mediates biliary cholesterol secretion independent of ATP-binding cassette transporter g5/g8 in mice

et al. 2009

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“…Also sPLA 2 is able to hydrolyze HDL phospholipids resulting in increased HDL catabolic rates and subsequently lower HDL cholesterol plasma levels (22,24). In addition, in vitro (23) and apparently also in vivo (23) selective uptake by SR-BI is increased following sPLA 2 modification of HDL. However, although sPLA 2 is only expressed at very low levels within the vascular wall in the absence of inflammation (29 -31), EL is even under steady-state noninflamed conditions a major modifier of HDL cholesterol plasma levels.…”

Section: Table 2 Hepatic Gene Expression Levels In Wild-type and Sr-bmentioning

confidence: 99%

Scavenger Receptor BI-mediated Selective Uptake Is Required for the Remodeling of High Density Lipoprotein by Endothelial Lipase

Nijstad

Wiersma

Gautier

et al. 2009

Journal of Biological Chemistry

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Endothelial lipase (EL) is a negative regulator of high density lipoprotein (HDL) cholesterol plasma levels, and scavenger receptor BI (SR-BI) is involved in remodeling of HDL. The present study investigates the requirement of SR-BI for the effects of EL-mediated phospholipid hydrolysis on HDL metabolism in vivo. In vitro, selective uptake from EL-modified HDL was 129% higher than selective uptake from control HDL in SR-BI-overexpressing cells (p ‫؍‬ 0.01). In vivo overexpression of human EL by means of recombinant adenovirus decreased HDL plasma levels significantly (p < 0.01). Fast protein liquid chromatography analysis and agarose gel electrophoresis revealed that EL expression resulted in the generation of small pre-␤ HDL particles in wild-type mice, whereas in SR-BI ؊/؊ mice small HDL were preferentially removed. In kinetic experiments the fractional catabolic rate (FCR) of HDL cholesteryl ester increased by 110% (p < 0.001), and the FCR of HDL apolipoproteins increased by 64% (p < 0.001) in response to EL overexpression in wild-type mice. In SR-BI ؊/؊ mice a similar increase in the HDL apolipoprotein FCR occurred (p < 0.001); however, there was no further increase in HDL cholesteryl ester catabolism. The apparent whole body selective uptake was increased 3-fold by EL in wild-type mice (p < 0.001), whereas there was no selective uptake in SR-BI knock-out mice. EL overexpression increased hepatic selective uptake as well as holoparticle uptake (each p < 0.01) in wild-type mice, whereas in SR-BI knock-out mice only holoparticle uptake increased (p < 0.01). Our results indicate that SR-BI-mediated selective uptake of HDL cholesteryl ester is essential for the remodeling of large ␣-migrating HDL particles by EL. Plasma levels of high density lipoprotein (HDL)3 cholesterol and its major apolipoprotein apoA-I are inversely correlated with the risk of atherosclerotic cardiovascular disease, a major cause of mortality in developed countries (1, 2). The factors responsible for the considerable variation in HDL cholesterol plasma levels are still incompletely understood. However, metabolic studies of HDL and apoA-I in humans have established that the substantial variation in their levels is primarily due to variation in the rate of apoA-I catabolism (3).Among the factors impacting on the remodeling and catabolism of HDL particles within the plasma compartment, the recently discovered endothelial lipase (EL) is of prime importance (4). EL is expressed in endothelial cells and macrophages, as well as in hepatocytes (5). EL has merely phospholipase and very little apparent triglyceridase activity (6), and HDL phospholipids represent a preferred substrate for the enzyme in in vitro assays (6, 7). The physiological relevance of EL-mediated hydrolysis of HDL particles for determining the plasma levels of HDL cholesterol has been established in experimental animals using both overexpression (5, 8) as well as loss-of-function models (9 -11). Overexpression of EL resulted in significantly decreased HDL cholesterol plasma leve...

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“…PCR primers and fl uorogenic probes were designed with the Primer Express Software (Applied Biosystems) and synthesized by Eurogentec (Seraing, Belgium). mRNA expression levels presented were calculated relative to the average of the housekeeping gene cyclophilin and further normalized to the relative expression level of the respective controls ( 9 ).…”

Section: Analysis Of Gene Expression By Real-time Quantitative Pcrmentioning

confidence: 99%

Scavenger receptor BI facilitates hepatic very low density lipoprotein production in mice

Wiersma

Nijstad

Gautier

et al. 2010

Journal of Lipid Research

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The scavenger receptor BI (SR-BI) is well characterized for its ability to mediate selective uptake of cholesteryl ester from HDL particles into cells ( 1, 2 ). Consistent with this role, SR-BI expression is highest in the liver and in steroidogenic tissues ( 1 ). Recently, SR-BI has also been implicated in the catabolism of apolipoprotein (apo)B-containing lipoproteins such as chylomicrons and ␤ -VLDLs by hepatocytes ( 3-6 ). However, the fi rst study demonstrating that adenovirus-mediated SR-BI overexpression increases the HDL catabolic rate indicated that plasma levels of apoB-containing lipoproteins actually increased significantly over time, whereas HDL levels remained low ( 7 ). Interestingly, hepatic LDL receptor (LDLR) expression was unchanged in this study during the course of the experiment ( 7 ). These data suggest, in our view, the possibility that SR-BI might be involved in hepatic cholesterol secretion.Therefore, we hypothesized that SR-BI might facilitate hepatic VLDL production, providing a potential link between the HDL and the apoB-containing lipoprotein cholesterol pathways. Our data demonstrate that hepatic VLDL-triglyceride as well as VLDL-apoB production in vivo are decreased in SR-BI knockout mice and increased following SR-BI overexpression. The results of our study further indicate that HDL-derived cholesterol is to a certain extent resecreted by hepatocytes as a component of VLDL particles in a process dependent on SR-BI expression.Abstract Scavenger receptor BI (SR-BI) is a selective uptake receptor for HDL cholesterol but is also involved in the catabolism of apolipoprotein (apo)B-containing lipoproteins. However, plasma levels of apoB-containing lipoproteins increase following hepatic SR-BI overexpression, suggesting that SR-BI not solely mediates their catabolism. We therefore tested the hypothesis that hepatic SR-BI impacts on VLDL production. On day 7 following adenovirus (Ad)-mediated overexpression of SR-BI, VLDL-triglyceride and VLDL-apoB production rates were signifi cantly increased ( P < 0.001), whereas VLDL production was significantly lower in SR-BI knockout mice compared with controls ( P < 0.05). In mice injected with AdSR-BI, hepatic cholesterol content increased ( P < 0.001), microsomal triglyceride transfer protein activity was higher ( P < 0.01) and expression of sterol-regulatory element binding protein (SREBP)2 and its target genes was decreased ( P < 0.01). Conversely, in SR-BI knockout mice, microsomal triglyceride transfer protein activity was lower and expression of SREBP2 target genes was increased ( P < 0.01). Finally, we demonstrate in vitro in isolated primary hepatocytes as well as in vivo that cholesterol derived from HDL and taken up via SR-BI into the liver can be resecreted within VLDL. These data indicate that hepatic SR-BI expression is linked to VLDL production, and within liver, a metabolic shunt might exist that delivers HDL cholesterol, at least in part, to a pool from which cholesterol is mobilized for VLDL production. These results might have i...

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Secretory phospholipase A2 increases SR-BI-mediated selective uptake from HDL but not biliary cholesterol secretion

Cited by 22 publications

References 40 publications

Scavenger receptor class B type I mediates biliary cholesterol secretion independent of ATP-binding cassette transporter g5/g8 in mice

Scavenger receptor class B type I mediates biliary cholesterol secretion independent of ATP-binding cassette transporter g5/g8 in mice

Scavenger Receptor BI-mediated Selective Uptake Is Required for the Remodeling of High Density Lipoprotein by Endothelial Lipase

Scavenger receptor BI facilitates hepatic very low density lipoprotein production in mice

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