High Density Lipoprotein Uptake by Scavenger Receptor SR-BII

Eckhardt, Erik; Cai, Lei; Sun, Bing; Webb, Nancy R.; Westhuyzen, Deneys R. van der

doi:10.1074/jbc.m313793200

Cited by 99 publications

(108 citation statements)

References 46 publications

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“…SR-BI-mediated internalization of apoA-I from HDL has been shown in both murine and human hepatocytes (33) and Madin-Darby canine kidney cells (34). However, little if any SR-BI-mediated uptake of HDL particles or apolipoproteins is observed in CHO cells (25,26) or steroidogenic cells (25,35), in which SR-BI levels and rates of HDL-selective uptake are high. In such cells, therefore, selective uptake does not appear to depend on internalization.…”

Section: Discussionmentioning

confidence: 99%

Serum Amyloid A Is a Ligand for Scavenger Receptor Class B Type I and Inhibits High Density Lipoprotein Binding and Selective Lipid Uptake

Cai

Beer

et al. 2005

Journal of Biological Chemistry

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161

141

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Serum amyloid A is an acute phase protein that is carried in the plasma largely as an apolipoprotein of high density lipoprotein (HDL). In this study we investigated whether SAA is a ligand for the HDL receptor, scavenger receptor class B type I (SR-BI), and how SAA may influence SR-BI-mediated HDL binding and selective cholesteryl ester uptake. Studies using Chinese hamster ovary cells expressing SR-BI showed that 125 Ilabeled SAA, both in lipid-free form and in reconstituted HDL particles, functions as a high affinity ligand for SR-BI. SAA also bound with high affinity to the hepatocyte cell line, HepG2. Alexa-labeled SAA was shown by fluorescence confocal microscopy to be internalized by cells in a SR-BI-dependent manner. To assess how SAA association with HDL influences HDL interaction with SR-BI, SAA-containing HDL was isolated from mice overexpressing SAA through adenoviral gene transfer. SAA presence on HDL had little effect on HDL binding to SR-BI but decreased (30 -50%) selective cholesteryl ester uptake. Lipid-free SAA, unlike lipid-free apoA-I, was an effective inhibitor of both SR-BI-dependent binding and selective cholesteryl ester uptake of HDL. We have concluded that SR-BI plays a key role in SAA metabolism through its ability to interact with and internalize SAA and, further, that SAA influences HDL cholesterol metabolism through its inhibitory effects on SR-BI-mediated selective lipid uptake.

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Section: Discussionmentioning

confidence: 99%

Serum Amyloid A Is a Ligand for Scavenger Receptor Class B Type I and Inhibits High Density Lipoprotein Binding and Selective Lipid Uptake

Cai

Beer

et al. 2005

Journal of Biological Chemistry

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161

141

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“…Proteins were dissociated from the pellet by boiling with SDS loading buffer and analyzed by SDS-PAGE and immunoblotting using anti-SR-BI antibody recognizing the C-terminal tail of SR-BI. 9 …”

Section: Biotinylation Of Surface Sr-bimentioning

confidence: 99%

“…9 Cell lysates (25 to 50 g) were incubated with 50 L of BSAblocked streptavidin beads suspension (Novagen) for 16 hours at 4°C and pelleted by centrifugation; the supernatant and pellet represent intracellular and surface proteins, respectively. Proteins were dissociated from the pellet by boiling with SDS loading buffer and analyzed by SDS-PAGE and immunoblotting using anti-SR-BI antibody recognizing the C-terminal tail of SR-BI.…”

Section: Biotinylation Of Surface Sr-bimentioning

confidence: 99%

“…5,6 In polarized cells, SR-BI is known to be localized largely at the plasma membrane, either apically (eg, enterocytes 7 ) or basolaterally (eg, hepatocytes 8 and MadinDarby canine kidney [MDCK] cells 9 ). Several reports have indicated that SR-BI functions as an endocytic receptor, particularly in polarized cells such as hepatocytes 8 and kidney (MDCK) 10 cells, and it has been proposed that selective lipid uptake from HDL occurs during SR-BI-mediated HDL recycling within cells.…”

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confidence: 99%

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Phosphatidylinositol-3-Kinase Regulates Scavenger Receptor Class B Type I Subcellular Localization and Selective Lipid Uptake in Hepatocytes

Shetty

Eckhardt

Post

et al. 2006

ATVB

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Objective-The high-density lipoprotein (HDL) receptor scavenger receptor Class B type I (SR-BI) plays a key role in mediating the final step of reverse cholesterol transport. This study examined the possible regulation of hepatic SR-BI by phosphatidylinositol-3-kinase (PI3K), a well known regulator of endocytosis and membrane protein trafficking. Methods and Results-SR-BI-dependent HDL selective cholesterol ester uptake in human HepG2 hepatoma cells was decreased (Ϸ50%) by the PI3K inhibitors wortmannin and LY294002. Insulin increased selective uptake (Ϸ30%), and this increase was blocked by PI3K inhibitors. Changes in SR-BI activity could be accounted for by pronounced changes in the subcellular localization and cell surface expression of SR-BI as determined by HDL cell surface binding, receptor biotinylation studies, and confocal fluorescence microscopy of HepG2 cells expressing green fluorescent protein-tagged SR-BI. Thus, under conditions of PI3K activation by insulin, and to a lesser extent by the SR-BI ligand HDL, cell surface expression of SR-BI was promoted, resulting in increased SR-BI-mediated HDL selective lipid uptake. Conclusion-Our

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“…The activity of PDZK1 can be modulated by phosphorylation near its C terminus (35). Its most N-terminal PDZ domain, PDZ1, binds to the carboxyl terminus of SR-BI (31, 36) but apparently not to a minor, alternatively spliced form of SR-BI called SR-BII, whose 39-residue C-terminal sequence (encoded by an alternatively spliced exon) differs from that of [37][38][39][40][41]. Unlike the four C-terminal residues in murine SR-BI (EAKL), those in SR-BII (SAMA) are not expected to bind to PDZ domains (42).…”

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confidence: 99%

Overexpression of the PDZ1 Domain of PDZK1 Blocks the Activity of Hepatic Scavenger Receptor, Class B, Type I by Altering Its Abundance and Cellular Localization

Fenske

Yesilaltay

Pal

et al. 2008

Journal of Biological Chemistry

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PDZK1 is a four-PDZ domain-containing scaffold protein that, via its first PDZ domain (PDZ1), binds to the C terminus of the high density lipoprotein (HDL) receptor scavenger receptor, class B, type I (SR-BI). Abolishing PDZK1 expression in PDZK1 knock-out (KO) mice leads to a post-transcriptional, tissue-specific decrease in SR-BI protein level and an increase in total plasma cholesterol carried in abnormally large HDL particles. Here we show that, although hepatic overexpression of PDZK1 restored normal SR-BI protein abundance and function in PDZK1 KO mice, hepatic overexpression of only the PDZ1 domain was not sufficient to restore normal SR-BI function. In wild-type mice, overexpression of the PDZ1 domain overcame the activity of the endogenous hepatic PDZK1, resulting in a 75% reduction in hepatic SR-BI protein levels and intracellular mislocalization of the remaining SR-BI. As a consequence, the plasma lipoproteins in PDZ1 transgenic mice resembled those in PDZK1 KO mice (hypercholesterolemia due to large HDL). These results indicate that the PDZ1 domain can control the abundance and localization, and therefore the function, of hepatic SR-BI and that structural features of PDZK1 in addition to its SR-BI-binding PDZ1 domain are required for normal hepatic SR-BI regulation.The high density lipoprotein (HDL) 3 receptor SR-BI (scavenger receptor, class B, type I) plays a key role in lipoprotein metabolism (1) by mediating the cellular uptake of cholesteryl esters from HDL and other lipoproteins into cells (2-7) via a mechanism called selective lipid uptake (3, 8 -10). SR-BI also mediates bidirectional flux of unesterified cholesterol between cells and lipoproteins (11)(12)(13)(14).Most in vivo analyses of the physiological function of SR-BI have been conducted in mice. SR-BI is highly expressed in the liver and steroidogenic tissues (adrenal gland, ovary, and testis), which exhibit the highest levels of HDL cholesterol uptake (3). Experimental manipulations of murine SR-BI expression (e.g. hepatic overexpression, homozygous null gene knock-out) can lead to changes in total plasma cholesterol levels, the ratio of plasma unesterified to total cholesterol, HDL structure, biliary cholesterol secretion, the amounts of cholesterol stored in steroidogenic tissues, and susceptibility to atherosclerosis (15-27). Homozygous null SR-BI knock-out mice exhibit abnormally elevated (ϳ2.2-fold) plasma cholesterol in large HDL particles with a unesterified cholesterol/total cholesterol ratio roughly double that of wild-type (WT) mice (19,52). This dyslipidemia is associated with female infertility and defects in the maturation and/or structure as well as reductions in the survival times of red blood cells (21,28,29,30).To date, only one intracellular protein has been shown to interact directly with and influence the function of SR-BI (31). This protein, PDZK1, regulates SR-BI expression in a tissuespecific, post-transcriptional manner (32). PDZK1 is a scaffold protein containing four PDZ protein interaction domains (Fig. 1A...

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High Density Lipoprotein Uptake by Scavenger Receptor SR-BII

Cited by 99 publications

References 46 publications

Serum Amyloid A Is a Ligand for Scavenger Receptor Class B Type I and Inhibits High Density Lipoprotein Binding and Selective Lipid Uptake

Serum Amyloid A Is a Ligand for Scavenger Receptor Class B Type I and Inhibits High Density Lipoprotein Binding and Selective Lipid Uptake

Phosphatidylinositol-3-Kinase Regulates Scavenger Receptor Class B Type I Subcellular Localization and Selective Lipid Uptake in Hepatocytes

Overexpression of the PDZ1 Domain of PDZK1 Blocks the Activity of Hepatic Scavenger Receptor, Class B, Type I by Altering Its Abundance and Cellular Localization

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