Disease relevance of SCARB1

• Finally, E2 recognition by SR-BI was competed out in an isolate-specific manner both on the hepatoma cell line and on the human SR-BI-transfected cell line by an anti-HVR1 monoclonal antibody [1].
• RESULTS: SR-BI expression was decreased in macrophages after hypoxia (p < 0.005) [2].
• We tested for a significant contribution of common variant of these genes to coronary heart disease (CHD) risk and hypothesized that genetic-mediated PON activity and CLA-1/SR-BI receptor functional properties jointly reduce plasma oxidation status [3].
• The scavenger receptor class B type I (SR-BI) has recently been shown to interact with hepatitis C virus (HCV) envelope glycoprotein E2, suggesting that it might be involved at some step of HCV entry into host cells [4].
• With respect to efflux of cholesterol, the mRNA levels of NCEH and ABCA-1 were unchanged, whereas CLA-1 mRNA was slightly higher in atheroma [5].

High impact information on SCARB1

• Studies of genetically manipulated strains of mice have established that SR-BI plays a key role in regulating lipoprotein metabolism and cholesterol transport to steroidogenic tissues and to the liver for biliary secretion [6].
• The role of the high-density lipoprotein receptor SR-BI in the lipid metabolism of endocrine and other tissues [6].
• In addition, analysis of SR-BI-deficient mice has shown that SR-BI expression is important for alpha-tocopherol and nitric oxide metabolism, as well as normal red blood cell maturation and female fertility [6].
• HDL also induces multiple cellular signals, which in endothelium occur through SR-BI and converge to activate eNOS [7].
• HDL-associated estradiol stimulates endothelial NO synthase and vasodilation in an SR-BI-dependent manner [8].

Chemical compound and disease context of SCARB1

• We show using detergent-free sucrose gradients that SR-BI is found in membrane rafts devoid of caveolin-1 in the human hepatoma HepG2 cell [9].
• In seminoma and spermatocytic seminoma, neoplastic cells labeled to HSL but failed to stain with antilipid receptors; in the seminiferous tubules at the periphery of the tumour, Charcot-Böttcher crystalloids of Sertoli cells were strongly positive to CLA-1 [10].
• TNF and IL-1 also decreased SR-BI levels in Hep3B hepatoma cells [11].
• Furthermore, SR-BI mRNA was expressed to similar levels in human primary adrenocortical and adrenocortical carcinoma NCI-H295 cells, indicating its presence in the steroid-producing cells [12].
• Although probucol could stabilize even murine SR-BI, when transfected into a human cell line, HepG2, human SR-BI was not stabilized in a mouse hepatoma cell line, Hepa 1-6, treated with probucol [13].

Biological context of SCARB1

• In contrast to known ligand-dependent apoptotic pathways, SR-BI-induced apoptosis is ligand-independent [14].
• Further studies revealed that the sequenced cDNA clone may result by alternative splicing from a longer mRNA form having an insertion of 300 nucleotides located 126 nucleotides downstream from the initiation codon of cloned CLA-1 [15].
• We found that liver-type fatty acid binding protein expression level is higher in SR-BI-overexpressing cells and that caveolin-1 and sterol response element binding protein-2 levels are reduced [9].
• The SR-BI-apoE interactions may contribute to overall cholesterol homeostasis in cells and tissues that express SR-BI and apoE [16].
• Thus our results demonstrate that EDL mediates both HDL binding and uptake, and the selective uptake of HDL-CE, independently of lipolysis and CLA-1 [17].

Anatomical context of SCARB1

• We have identified the receptor responsible for E2 binding to human hepatic cells as the human scavenger receptor class B type I (SR-BI) [1].
• When HDL levels are low, oxidative stress causes the relocation of eNOS away from caveolae, which turns on SR-BI-induced apoptosis and rapidly clears damaged cells to prevent further inflammatory damage to neighboring cells [14].
• In both cultivated HepG2 hepatocytes and primary human monocyte-derived macrophages, testosterone led to a dose-dependent up-regulation of SR-BI, which was assessed on both the mRNA and the protein levels [18].
• Furthermore, immunohistochemical analysis showed that immunoreactive mass of hSR-BI was detected in foam cells in human aortic atherosclerotic lesions and that there was no significant difference of staining patterns between the two Abs [19].
• We propose that this direct interaction could modify SR-BI structure in cell membranes and potentiate CE uptake [20].

Associations of SCARB1 with chemical compounds

• In Chinese hamster ovary cells, SAA promoted cellular cholesterol efflux in an SR-BI-dependent manner, whereas apoA-I did not [21].
• To assess the effect of SAA on SR-BI-mediated efflux to high density lipoprotein (HDL), we compared normal HDL, acute phase HDL (AP-HDL, prepared from mice injected with lipopolysaccharide), and AdSAA-HDL (HDL prepared from mice overexpressing SAA) [21].
• A mutant SR-BI (SR-BIdel509) that lacked only the leucine in the PDZ-interacting domain failed to interact with PDZK1 in vitro, while showing normal selective uptake function in nonpolarized cells [22].
• In line with the ligand-binding specificity of CLA-1, phosphatidylcholine did not compete for selective HDL(3)-CE uptake [23].
• Competition experiments demonstrated that CLA-1 ligands (oxidized HDL, oxidized and acetylated low-density lipoprotein and phosphatidylserine) inhibited selective HDL(3)-CE uptake [23].

Physical interactions of SCARB1

• In an effort to elucidate the role of this interaction in vivo, the PDZK1-interacting domain of SR-BI was identified and mutated and expressed liver-specifically in mice [22].
• SR-BI mediates cholesterol efflux via its interactions with lipid-bound ApoE. Structural mutations in SR-BI diminish cholesterol efflux [16].
• We demonstrate that this functional HDL/SR-BI interaction only interferes with antibodies blocking HCV-E2 binding to CD81, a major HCV receptor, reflecting its prominent role during the cell entry process [24].
• Thus, CD36 has been reported to bind oxidized LDL (OxLDL) and acetylated LDL (AcLDL), while SR-BI also binds native LDL and HDL [25].
• The data confirmed that E2 through the ERs can positively regulate the HDL-R SR-BI through binding and activation of three ERE(1/2) motifs and identified SREBP-1a as a potential coactivator of the E2-ER-dependent effects on the HDL-R SR-BI gene [26].

Regulatory relationships of SCARB1

• We conclude that SR-BII may influence cellular cholesterol trafficking and homeostasis in a manner that is distinct from SR-BI [27].
• We conclude that HDL binding to SR-BI stimulates eNOS by increasing intracellular ceramide levels and is independent of an increase in intracellular calcium or Akt kinase phosphorylation [28].
• Here we show that PDZK1 controls in a tissue-specific and post-transcriptional fashion the expression of SR-BI in vivo [29].
• LPL stimulated [3H]cholesteryl oleyl ether uptake from labeled HDL3 by HEK 293 cells substantially, showing that LPL can induce selective CE uptake from HDL3 independent of SR-BI [30].

Other interactions of SCARB1

• Identification, primary structure, and distribution of CLA-1, a novel member of the CD36/LIMPII gene family [15].
• Apolipoprotein E (apoE) and the lipoprotein receptor SR-BI play critical roles in lipid and lipoprotein metabolism [16].
• These data, together with the phylogenetic analysis carried out for the members of this family, indicate that the LIMPII, CLA-1, and CD36 genes diverged early in evolution from an ancestor gene, possibly before the divergence between the arthropods and the vertebrates [31].
• CONCLUSION: Two complementary cellular models providing SR-BI and ABCA1-dependent efflux should be used to measure the capacity of a biological fluid which contains a wide variety of components to promote cholesterol efflux [32].
• Thus, in this hepatic cell model, SR-BI is associated with membrane rafts devoid of caveolin and its expression affects intracellular lipid binding and lipid sensor proteins [9].

Analytical, diagnostic and therapeutic context of SCARB1

• Northern blot analysis indicates that CLA-1 is widely expressed although its mRNA steady state levels vary considerably among the analyzed cell types [15].
• Alexa-labeled SAA was shown by fluorescence confocal microscopy to be internalized by cells in a SR-BI-dependent manner [33].
• SR-BI and SR-BII proteins were also detected by immunofluorescence staining of RPE cells in culture [34].
• SR-BI protein was detected by immune precipitation of [(35)S]methionine-labeled crude cellular extracts [34].
• Expression of SR-BI isoforms was characterized in human atherosclerotic plaques and macrophages using RT-PCR and DNA sequencing [2].

References