Disease relevance of Scarb1

• Scavenger receptor BI protects against septic death through its role in modulating inflammatory response [1].
• Scavenger receptor BI prevents nitric oxide-induced cytotoxicity and endotoxin-induced death [2].
• On cessation of the treatment SR-BI expression returns to its pretreatment levels, coinciding with a reversal of the hypercholesterolemia to base-line concentrations [3].
• Sepsis also down-regulates SR-B1 [4].
• Surprisingly, elimination of SR-BI in apolipoprotein E knockout mice results in rapid development of occlusive coronary artery disease, accompanied by spontaneous myocardial infarction, reduced heart function and early death, which points to a role for SR-BI in protection against coronary heart disease [5].
• To assess the role of the class B scavenger receptor CD36 in atherogenesis, we crossed a CD36-null strain with the atherogenic apo E-null strain and quantified lesion development [6].
• Response to Staphylococcus aureus requires CD36-mediated phagocytosis triggered by the COOH-terminal cytoplasmic domain [7].

Psychiatry related information on Scarb1

• CONCLUSIONS: A genetic variant at the SR-BI gene promoter region might explain a significant proportion of individual differences in HDL-C levels among Taiwanese Chinese. Our results require further replication in an independent population [8].

High impact information on Scarb1

• Charting the fate of the "good cholesterol": identification and characterization of the high-density lipoprotein receptor SR-BI [9].
• This receptor, called scavenger receptor class B type I (SR-BI), is a fatty acylated glycoprotein that can cluster in caveolae-like domains on the surfaces of cultured cells [9].
• In wild-type macrophages, TZD treatment divergently regulated CD36 and class A macrophage-scavenger receptor expression and failed to induce significant cellular cholesterol accumulation, indicating that TZDs may not exacerbate macrophage foam-cell formation [10].
• Overexpression of the HDL receptor SR-BI alters plasma HDL and bile cholesterol levels [11].
• We show here that expression of the murine CD36 gene in B cells and macrophages requires a functional Oct-2 protein [12].

Chemical compound and disease context of Scarb1

• Sepsis syndrome stimulates proximal tubule cholesterol synthesis and suppresses the SR-B1 cholesterol transporter [4].
• However, when fed an atherogenic diet rich in fat, cholesterol, and cholate, they rapidly developed hypercholesterolemia, atherosclerosis, and CHD, a response strikingly similar to that of SR-BI/apoE dKO mice fed a chow diet, and they died 32+/-6 days (50% mortality) after initiation of the high-fat feeding [13].
• The effect of PG on the proliferation and apoptosis of the B16F10 melanoma cell line was determined by a sulforhodamine B (SRB) and a sandwich enzyme-linked immunosorbent assay [14].

Biological context of Scarb1

• We now show up-regulation of adrenal SR-BI mRNA and protein in apoA-I0 mice, but not in apoA-II0, LDL receptor 0, apoE0, or cholesteryl ester transfer protein transgenic mice [15].
• SR-BI-apoE interactions may contribute to cholesterol homeostasis in tissues and cells expressing SR-BI that are accessible to apoE-containing lipoproteins [16].
• In the present investigation we report that ciprofibrate treatment causes the down-regulation of hepatic scavenger receptor class B, type I (SR-BI) protein expression in the livers of apoE-deficient mice [3].
• After a meal containing [(14)C]cholesterol and [(3)H]triolein, SR-BI transgenic mice presented a rise in intestinal absorption of both lipids that was not due to a defect in chylomicron clearance nor to a change in the bile flow or the bile acid content [17].
• We have generated transgenic mice overexpressing SR-BI primarily in the intestine by using the mouse SR-BI gene under the control of intestinal specific "apoC-III enhancer coupled with apoA-IV promoter." We found SR-BI overexpression with respect to the natural protein along the intestine and at the top of the villosities [17].

Anatomical context of Scarb1

• 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 [18].
• Binding was nearly abolished in a cell line expressing the ldlA (Q402R/Q418R) double mutant form of SR-BI that is unable to bind native high density lipoprotein but binds low density lipoprotein normally [16].
• Scavenger receptor BI (SR-BI), a putative high density lipoprotein (HDL) receptor, mediates the selective uptake of HDL cholesteryl ester into cells and is highly expressed in adrenal gland (Acton, S., Rigotti, A., Landschulz, K.T., Xu, S., Hobbs, H.H., and Krieger, M. (1996) Science 271, 518-520) [15].
• Thus, mSR-BI colocalizes with caveolae, and this raises the possibility that the unique properties of these specialized cell surface domains may play a critical role in SR-BI-mediated transfer of lipids between lipoproteins and cells [19].
• We also report that remnants isolated from the plasma of ciprofibrate-treated apoE-deficient mice bind to murine SR-BI expressed in stably transfected cultured cells [3].

Associations of Scarb1 with chemical compounds

• We speculate that SR-BI is in a more fluid membrane domain that will favor rapid cholesterol flux between the membrane and HDL [18].
• Nevertheless, SR-BI transgenic mice showed a decrease of total cholesterol but an increase of triglyceride content in plasma without any change in the high density lipoprotein apoA-I level [17].
• The treatment of lean control mice with troglitazone significantly increased the expression of adipocyte fatty acid-binding protein (aP2) and fatty acid translocase (FAT/CD36) in the liver [20].
• A similar reduction in HDL binding and CD36 message was also observed with the immunosuppressive glucocorticoid dexamethasone [21].
• Also, enhanced expression of ABC-A1 and SR-B1 in aortic macrophages may contribute to the antiatherosclerotic effect of fenofibrate by promoting cholesterol efflux [22].
• Glucocorticoid insufficiency in SR-BI-null mice was due to primary adrenal malfunction resulting from deficient cholesterol delivery from HDL [23].

Physical interactions of Scarb1

• RECENT FINDINGS: The PDZ domain-containing adaptor protein PDZK1 has been shown to bind to and control the activity of the high-density lipoprotein receptor SR-BI via a tissue-specific posttranscriptional mechanism [24].
• Conversely, loading macrophages with cholesterol or cholesteryl ester (acetate) with MebetaCD:cholesterol complexes increased CD36 mRNA, 125I-labeled OxLDL binding, and CD36 surface expression as determined by fluorescence activated cell sorting [25].

Regulatory relationships of Scarb1

• This troglitazone-induced increase in the expression of aP2 and FAT/CD36 was markedly enhanced in the liver in ob/ob mice [20].
• CONCLUSIONS: The increased hepatic CE levels, following P-407 treatment, was neither related to an up-regulation of ACAT2 nor enhanced SR-BI expression [26].
• Furthermore, selective elimination of SR-BI expression in bone marrow-derived cells resulted in increased diet-induced atherosclerosis in LDL receptor knockout mice without concomitant alterations in the distributions of plasma lipoprotein cholesterol [27].
• Low-density lipoprotein from apolipoprotein E-deficient mice induces macrophage lipid accumulation in a CD36 and scavenger receptor class A-dependent manner [28].
• These findings indicate that SR-BI expression may be influenced by changes in HL activity [29].

Other interactions of Scarb1

• Overexpression of SR-BI by adenoviral vector reverses the fibrateinduced hypercholesterolemia of apolipoprotein E-deficient mice [3].
• The action of hepatic lipase on apoA-I-containing lipoproteins may facilitate the SR-BI-mediated uptake of HDL lipid [15].
• Upon short-term (2 days) treatment with leptin, a dose-dependent increase was seen in the SR-BI protein and mRNA, whereas the Cyp7a1 protein and mRNA were reduced [30].
• In contrast to the liver, troglitazone did not increase the expression of aP2, FAT/CD36, and uncoupling protein-2 in adipose tissue in lean or ob/ob mice [20].
• It also suppressed expression of the 2 major scavenger receptors (scavenger receptor-A [SR-A] and CD36), in part by inhibiting IL-6, and inhibited macrophage foam cell formation [31].

Analytical, diagnostic and therapeutic context of Scarb1

• Electron microscopy showed SR-BI in patches or clusters primarily on microvillar extensions of the plasma membrane [18].
• Fluorescence confocal microscopy showed SR-BI in patches and small extensions of the cell surface that were distinct from sites of caveolin-1 expression [18].
• Adrenal SR-BI mRNA and protein are also increased and cholesterol stores decreased in female mice with knockout of hepatic lipase, and enzyme previously shown to increase selective uptake in cell culture [15].
• We have used bone-marrow transplantation to demonstrate that bone-marrow-derived SR-BI also normally protects against atherosclerosis in low-density lipoprotein receptor knockout mice [5].
• Characterization of aortic sinus lesions by electron microscopy and immunohistochemistry showed abundant macrophage foam cells, indicating that lipid uptake by intimal macrophages occurs in the absence of CD36 or SR-A [32].

References