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At least 19 recordsLinked to original sources

PubMed2003

Separation of lipid transport functions by mutations in the extracellular domain of scavenger receptor class B, type I.

Scavenger receptor class B, type I (SR-BI) shows a variety of effects on cellular cholesterol metabolism, including increased selective uptake of high density lipoprotein (HDL) cholesteryl ester, stimulation of free cholesterol (FC) efflux from cells to HDL and phospholipid vesicles, and changes in the distribution of plasma membrane FC as evidenced by increased susceptibility to exogenous cholesterol oxidase. Previous studies showed that these multiple effects require the extracellular domain of SR-BI, but not the transmembrane and cytoplasmic domains. To test whether 1) the extracellular domain of SR-BI mediates multiple activities by virtue of discrete functional subdomains, or 2) the multiple activities are, in fact, secondary to and driven by changes in cholesterol flux, the extracellular domain of SR-BI was subjected to insertional mutagenesis by strategically placing an epitope tag into nine sites. These experiments identified four classes of mutants with disruptions at different levels of function. Class 4 mutants showed a clear separation of function between HDL binding, HDL cholesteryl ester uptake, and HDL-dependent FC efflux on one hand and FC efflux to small unilamellar vesicles and an increased cholesterol oxidase-sensitive pool of membrane FC on the other. Selective disruption of the latter two functions provides evidence for multiple functional subdomains in the extracellular receptor domain. Furthermore, these findings uncover a difference in the SR-BI-mediated efflux pathways for FC transfer to HDL acceptors versus phospholipid vesicles. The loss of the cholesterol oxidase-sensitive FC pool and FC efflux to small unilamellar vesicle acceptors in Class 4 mutants suggests that these activities may be mechanistically related.

Amino Acid Sequence↗

PubMed2005

Increased plasma levels of LDL cholesterol in rabbits after adenoviral overexpression of human scavenger receptor class B type I.

Scavenger receptor class B type I (SR-BI), a CD36 family member, plays a key role in high-density lipoprotein (HDL) metabolism, reverse cholesterol transport, and whole body cholesterol homeostasis, and is shown to be involved in the development of atherosclerosis in mice. In this report, we describe the effects of the adenoviral overexpression of human SR-BI (hSR-BI) in New Zealand White (NZW) rabbits, a wild-type animal model that expresses cholesteryl ester transfer protein (CETP) in plasma, displays a manlike lipoprotein profile, and is susceptible to atherosclerosis. A total of 1x10(12) adenoviral particles containing either hSR-BI or lacZ complementary deoxyribonucleic acid (control) were infused into the ear vein of NZW rabbits. Transgene expression was ascertained by TaqMan Real Time polymerase chain reaction measurements. Rabbits infected with Ad/hSR-BI (adenoviral plasmids containing hSR-BI) showed a faster clearance of administered [3H]HDL cholesterol and significantly decreased apolipoprotein (apo) A-I levels when compared to control rabbits, respectively. Interestingly, we found markedly increased levels of low-density lipoprotein (LDL) cholesterol exclusively in SR-BI-overexpressing rabbits. These changes were not accompanied by alterations in LDL receptor expression but by increased levels of CE transfer in these animals. By lowering HDL cholesterol and increasing plasma apoB-containing lipoprotein levels, the overexpression of SR-BI leads to a lipoprotein pattern, which is believed to enhance the development of atherosclerosis. The role of SR-BI in lipoprotein metabolism and atherogenesis in rabbits--a CETP-expressing animal model displaying a manlike lipoprotein profile--may therefore be different from the one found in rodents.

Adenoviridae↗

PubMed2004

Remodeling of HDL remnants generated by scavenger receptor class B type I.

Scavenger receptor class B type I (SR-BI) mediates the selective transfer of cholesteryl ester from HDL to cells. We previously established that SR-BI overexpressed in livers of apolipoprotein A-I-deficient mice processes exogenous human HDL2 to incrementally smaller HDL particles. When mixed with normal mouse plasma either in vivo or ex vivo, SR-BI-generated HDL "remnants" rapidly remodel to form HDL-sized lipoproteins. In this study, we analyzed HDLs throughout the process of HDL remnant formation and investigated the mechanism of conversion to larger particles. Upon interacting with SR-BI, alpha-migrating HDL2 is initially converted to a prealpha-migrating particle that is ultimately processed to a smaller alpha-migrating HDL remnant. SR-BI does not appear to generate prebeta-1 HDL particles. When incubated with isolated lipoprotein fractions, HDL remnants are converted to lipoprotein particles corresponding in size to the particle incubated with the HDL remnant. HDL remnant conversion is not altered in phospholipid transfer protein (PLTP)-deficient mouse plasma or by the addition of purified PLTP. Although LCAT-deficient plasma promoted only partial conversion, this deficiency was attributable to the nature of HDL particles in LCAT-/- mice rather than to a requirement for LCAT in the remodeling process. We conclude that HDL remnants, generated by SR-BI, are converted to larger particles by rapidly reassociating with existing HDL particles in an enzyme-independent manner.

Animals↗

PubMed2001

Scavenger receptor class B type I-mediated reverse cholesterol transport is inhibited by advanced glycation end products.

Cellular interactions of advanced glycation end products (AGE) are mediated by AGE receptors. We demonstrated previously that class A scavenger receptor types I and II (SR-A) and CD36, a member of class B scavenger receptor family, serve as the AGE receptors. In this study, we investigated whether scavenger receptor class B type I (SR-BI), another receptor belonging to class B scavenger receptor family, was also an AGE receptor. We used Chinese hamster ovary (CHO) cells overexpressed hamster SR-BI (CHO-SR-BI cells). (125)I-AGE-bovine serum albumin (AGE-BSA) was endocytosed in a dose-dependent fashion and underwent lysosomal degradation by CHO-SR-BI cells. (125)I-AGE-BSA exhibited saturable binding to CHO-SR-BI cells (K(d) = 8.3 microg/ml). Endocytic uptake of (125)I-AGE-BSA by CHO-SR-BI cells was completely inhibited by oxidized low density lipoprotein (LDL) and acetylated LDL, whereas LDL exerted only a weak inhibitory effect (<20%). Cross-competition experiments showed that AGE-BSA had no effect on HDL binding to these cells and vice versa. Interestingly, however, SR-BI-mediated selective uptake of HDL-CE was completely inhibited by AGE-BSA in a dose-dependent manner (IC(50) <10 microg/ml). Furthermore, AGE-BSA partially inhibited (by <30%) the selective uptake of HDL-CE in human hepatocarcinoma HepG2 cells (IC(50) <30 microg/ml). In addition, [(3)H]cholesterol efflux from CHO-SR-BI cells to HDL was significantly inhibited by AGE-BSA in a dose-dependent manner (IC(50) <30 microg/ml). Our results indicate that AGE proteins, as ligands for SR-BI, effectively inhibit both SR-BI-mediated selective uptake of HDL-CE and cholesterol efflux from peripheral cells to HDL, suggesting that AGE proteins might modulate SR-BI-mediated cholesterol metabolism in vivo.

Animals↗

PubMed2001

Scavenger receptor class B type I (SR-BI) mediates adhesion of neonatal murine microglia to fibrillar beta-amyloid.

Class A scavenger receptors (SR-A) mediate microglial interaction with fibrillar beta-amyloid (fAbeta). We report here that neonatal microglia from SR-A knockout mice (SR-A-/-) adhere to surface-bound fAbeta, and produce reactive oxygen species (ROS) as efficiently as wildtype microglia; that both wildtype and SR-A-/- microglia express SR-BI; that antibodies against SR-BI do not affect adhesion or ROS production by wildtype microglia, but inhibit adhesion and ROS production of SR-A-/- microglia to immobilized fAbeta by approximately 40%. Adhesion to fAbeta-coated surfaces, and uptake of fAbeta by both wildtype and SR-A-/- microglia was almost completely inhibited by incubation with fucoidan. Thus SR-BI and SR-A mediate similar effector functions in neonatal microglia, which suggests that SR-BI plays as important a role as SR-A, and can maintain the wildtype phenotype in SR-A-/- microglia.

Alzheimer Disease↗

PubMed2002

Liver receptor homolog 1 controls the expression of the scavenger receptor class B type I.

The scavenger receptor class B type I (SR-BI), which mediates selective cellular cholesterol uptake from high-density lipoproteins (HDLs), plays a key role in reverse cholesterol transport. The orphan nuclear receptor liver receptor homolog 1 (LRH-1) and SR-BI are co-expressed in liver and ovary, suggesting that LRH-1 might control the expression of SR-BI in these tissues. LRH-1 induces human and mouse SR-BI promoter activity by binding to an LRH-1 response element in the promoter. Retroviral expression of LRH-1 robustly induces SR-BI, an effect associated with histone H3 acetylation on the SR-BI promoter. The decrease in SR-BI mRNA levels in livers of LRH-1(+/-) animals provides in vivo evidence that LRH-1 regulates SR-BI expression. Our data demonstrate that SR-BI is an LRH-1 target gene and underscore the pivotal role of LRH-1 in reverse cholesterol transport.

Animals↗

PubMed2005

High density lipoproteins facilitate hepatitis C virus entry through the scavenger receptor class B type I.

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. However, due to the absence of a cell culture system to efficiently amplify HCV, it is not clear how SR-BI contributes to HCV entry. Here, we sought to determine how high density lipoproteins (HDLs), the natural ligand of SR-BI, affect HCV entry. By using the recently described infectious HCV pseudotyped particles (HCVpps) that display functional E1E2 glycoprotein complexes, we showed that HDLs are able to markedly enhance HCVpp entry. We did not find any evidence of HDL association with HCVpps, suggesting that HCVpps do not enter into target cells using HDL as a carrier to bind to its receptor. Interestingly, lipid-free apoA-I and apoA-II, the major HDL apolipoproteins, were unable to enhance HCVpp infectivity. In addition, drugs inhibiting HDL cholesteryl transfer (block lipid transport (BLT)-2 and BLT-4) reduced HDL enhancement of HCVpp entry, suggesting a role for lipid transfer in facilitating HCVpp entry. Importantly, silencing of SR-BI expression in target cells by RNA interference markedly reduced HDL-mediated enhancement of HCVpp entry. Finally, enhancement of HCVpp entry was also suppressed when the SR-BI binding region on HCV glycoprotein E2 was deleted. Altogether, these data indicate that HDL-mediated enhancement of HCVpp entry involves a complex interplay between SR-BI, HDL, and HCV envelope glycoproteins, and they highlight the active role of HDLs in HCV entry.

CD36 Antigens↗

PubMed2000

Identification of a PDZ-domain-containing protein that interacts with the scavenger receptor class B type I.

The scavenger receptor class B type I (SR-BI) mediates the selective uptake of cholesteryl esters from high-density lipoprotein (HDL) and cholesterol secretion into bile in the liver. In this study, we identified an SR-BI-associated protein from rat liver membrane extracts by using an affinity chromatography technique. This protein of 523 amino acids contains four PDZ domains and associates with the C terminus of SR-BI by using its N-terminal first PDZ domain. Therefore, we denoted this protein as CLAMP (C-terminal linking and modulating protein). CLAMP was located mostly in the sinusoidal membranes, whereas SR-BI was detected in both sinusoidal and canalicular membranes. After the solubilization of the liver membranes with Triton X-100, SR-BI was immunoprecipitated with anti-CLAMP monoclonal antibody, suggesting the association of these proteins in vivo. By coexpressing SR-BI with CLAMP in Chinese hamster ovary cells, we observed (i) the increase in the expression level of SR-BI, (ii) the reduction in the deacylation rate of the cholesteryl esters taken up from HDL, and (iii) the change in the intracellular distribution of fluorescent lipid 1,1'-dioctadecyl-3,3, 3',3'-tetramethylindocarbocyanine percholate taken up from HDL. Taken together, these data suggest that CLAMP, a four-PDZ-domain-containing protein, is associated with SR-BI in the liver sinusoidal plasma membranes and may modulate the intracellular transport and metabolism of cholesteryl esters taken up from HDL.

Amino Acid Sequence↗

PubMed1997

High affinity saturable uptake of oxidized low density lipoprotein by macrophages from mice lacking the scavenger receptor class A type I/II.

Oxidation of low density lipoproteins (LDL) has been implicated as a causal factor in the pathogenesis of atherosclerosis. Oxidized LDL has been found to exhibit numerous potentially atherogenic properties in vitro, including receptor-mediated uptake by macrophages. Oxidized LDL is a ligand for the class A scavenger receptor type I/II (SR-AI/II), but cross-competition studies with cultured macrophages suggested that there is an additional receptor(s) that is specific for oxidized LDL and that does not interact with acetyl LDL or other chemically modified LDL. A number of macrophage membrane proteins, including CD36, FcgammaRII-B2, scavenger receptor BI, and macrosialin/CD68, have been found to bind to oxidized LDL in vitro and have been proposed as candidate oxidized LDL receptors. However, because of overlapping ligand specificity with the SR-AI/II, it has been difficult to evaluate the relative importance of these proteins in the uptake of oxidized LDL by macrophages. In the present report, we have studied the uptake and degradation of oxidized LDL by macrophages from mice in which the SR-AI/II gene had been disrupted. The uptake of acetyl LDL was reduced by more than 80% in macrophages from scavenger receptor knockout mice, confirming that most of the uptake of acetyl LDL by macrophages can be attributed to this receptor. In contrast, the uptake of extensively oxidized LDL was reduced by only 30% and showed high affinity, saturable uptake with apparent Km of about 5 microg/ml, similar to that of the SR-AI/II. This indicates that about 70% of the uptake of oxidized LDL in macrophages is attributable to an alternate oxidized LDL receptor(s). In contrast to findings reported with CD36, mildly oxidized LDL was internalized much more slowly than extensively oxidized LDL. Unlabeled oxidized LDL, polyinosinic acid, phosphatidylserine-rich liposomes, and LDL or bovine albumin modified by fatty acid oxidation products were effective competitors for the uptake of radioiodinated oxidized LDL by macrophages from knockout mice, whereas acetyl LDL and malondialdehyde-modified LDL were relatively poor competitors. This ligand specificity differs from that of CD36-related (class B) scavenger receptors but is similar to the reported specificity of macrosialin/CD68 in ligand blots. However, the rate of uptake of oxidized LDL by knockout macrophages was not increased by phorbol ester or in thioglycollate-elicited macrophages, both of which are expected to increase the amount of macrosialin on the cell surface. In macrophages from SR-AI/II knockout mice, ligand blots of membrane proteins with iodinated, oxidized, or acetylated LDL revealed several bands, with apparent molecular size on SDS-polyacrylamide gel electrophoresis of 60, 94, 124, and 210 kDa, but none of the bands were specific for oxidized LDL. These results provide direct evidence that a receptor other than SR-AI/II is responsible for most of the uptake of oxidized LDL in murine macrophages, but further studies are needed to identify the receptor(s) involved.

Animals↗

PubMed2004

Visualization of the uptake of individual HDL particles in living cells via the scavenger receptor class B type I.

The scavenger receptor class B type I (SR-BI) plays an important role in mediating selective uptake of high-density lipoprotein (HDL)-derived cholesterol and cholesteryl ester in liver and steroidogenic tissues. The molecular mechanism by which this receptor mediates selective cholesteryl ester uptake remains still enigmatic. We applied ultrasensitive fluorescence microscopy to visualize the intracellular transport routes of HDL particles taken up via SR-BI in a Chinese hamster ovarian cell line. Although diffusion of the receptor bound particles on the cell surface is slow, internalization is accompanied by a dramatic increase in the mobility of the particles. HDL particles are endocytosed as clusters and actively transported to the perinuclear region of the cell. Costaining with organelle markers confirmed the involvement of an acidic compartment and the Golgi apparatus in the uptake process; finally, resecretion of the HDL particles was observed.

Animals↗

PubMed2001

The cellular biology of scavenger receptor class B type I.

The HDL receptor scavenger receptor class B type I plays an important role in meditating the uptake of HDL-derived cholesterol and cholesteryl ester in the liver and steroidogenic tissues. However, the mechanism by which scavenger receptor class B type I mediates selective cholesterol uptake is unclear. In hepatocytes scavenger receptor class B type I mediates the transcytosis of cholesterol into bile, appears to be expressed on both basolateral and apical membranes, and directly interacts with a PDZ domain containing protein that may modulate the activity of scavenger receptor class B type I. This suggests the involvement of scavenger receptor class B type I in higher order complexes in polarized cells. Scavenger receptor class B type I expression has been shown to alter plasma membrane cholesterol distribution and induce the formation of novel membrane structures, suggesting multiple roles for scavenger receptor class B type I in the cell. A close examination of scavenger receptor class B type I function in polarized cells may yield new insights into the mechanism of scavenger receptor class B type I-mediated HDL selective uptake and the effects of scavenger receptor class B type I on cellular cholesterol homeostasis.

Animals↗

PubMed2001

Localization of CD36 and scavenger receptor class A in human coronary arteries--a possible difference in the contribution of both receptors to plaque formation.

CD36 and scavenger receptor class A types I and II (SR-AI/II) are major receptors for oxidized low density lipoproteins (OxLDL) expressed on macrophages. To elucidate the role of these two macrophage scavenger receptors in the development of coronary atherosclerosis, we examined the localization of CD36 and SR-AI/II in human coronary atherosclerotic lesions. Serial cryostat sections of 49 coronary arteries obtained from 43 autopsied cases were examined immunohistochemically. Regarding the relationship between the severity of atherosclerosis and immunoreactivities to CD36, there was almost no immunoreactivity to CD36 in regions with diffuse intimal thickening, while the expression of CD36 was accelerated in parallel with the progression of atherosclerosis. In contrast, SR-AI/II was expressed persistently from regions with diffuse intimal thickening to atherosclerotic plaques. We also clarified the differential distribution of CD36 and SR-AI/II in atheromatous plaques. Close to the luminal surface of the intima, macrophages were relatively small in size, contained lesser lipids, and expressed SR-AI/II more abundantly than CD36. In contrast, macrophages in the core region were larger in size, contained more lipids, were strongly positive for CD36 and showed a weaker immunoreactivity to SR-AI/II than those in the luminal surface of the intima. In conclusion, the expression of CD36 and SR-AI/II on macrophages may be regulated differently in the process of coronary atherogenesis.

Adolescent↗

PubMed1999

Developmental and hormonal regulation of murine scavenger receptor, class B, type 1.

The scavenger receptor, class B, type I (SR-BI), is the predominant receptor that supplies plasma cholesterol to steroidogenic tissues in rodents. We showed previously that steroidogenic factor-1 (SF-1) binds a sequence in the human SR-BI promoter whose integrity is required for high-level SR-BI expression in cultured adrenocortical tumor cells. We now provide in vivo evidence that SF-1 regulates SR-BI. During mouse embryogenesis, SR-BI mRNA was initially expressed in the genital ridge of both sexes and persisted in the developing testes but not ovary. This sexually dimorphic expression profile of SR-BI expression in the gonads mirrors that of SF-1. No SR-BI mRNA was detected in the gonadal ridge of day 11.5 SF-1 knockout embryos. Both SR-BI and SF-1 mRNA were expressed in the cortical cells of the nascent adrenal glands. These studies directly support SF-1 participating in the regulation of SR-BI in vivo. We examined the effect of cAMP on SR-BI mRNA and protein in mouse adrenocortical (Y1-BS1) and testicular carcinoma Leydig (MA-10) cells. The time courses of induction were strikingly similar to those described for other cAMP- and SF-1-regulated genes. Addition of lipoproteins reduced SR-BI expression in Y1-BS1 cells, an effect that was reversed by administration of cAMP analogs. SR-BI mRNA and protein were expressed at high levels in the adrenal glands of knockout mice lacking the steroidogenic acute regulatory protein; these mice have extensive lipid deposits in the adrenocortical cells and high circulating levels of ACTH. Taken together, these studies suggest that trophic hormones can override the suppressive effect of cholesterol on SR-BI expression, thus ensuring that steroidogenesis is maintained during stress.

Adrenal Glands↗

PubMed2002

Hypochlorite-modified high density lipoprotein, a high affinity ligand to scavenger receptor class B, type I, impairs high density lipoprotein-dependent selective lipid uptake and reverse cholesterol transport.

Hypochlorous acid/hypochlorite (HOCl/OCl(-)), a potent oxidant generated in vivo by the myeloperoxidase-H(2)O(2)-chloride system of activated phagocytes, alters the physiological properties of high density lipoprotein (HDL) by generating a proatherogenic lipoprotein particle. On endothelial cells lectin-like oxidized low density lipoprotein receptor 1 (LOX-1) and scavenger receptor class B, type I (SR-BI), act in concert by mediating the holoparticle of and selective cholesteryl ester uptake from HOCl-HDL. We therefore investigated the ligand specificity of HOCl-HDL to SR-BI-overexpressing Chinese hamster ovary cells. Binding of HOCl-HDL was saturable, and the degree of HOCl modification was the determining factor for increased binding affinity to SR-BI. Competition experiments further confirmed that HOCl-HDL binds with increased affinity to the same or overlapping domain(s) of SR-BI as does native HDL. Furthermore, SR-BI-mediated selective HDL-cholesteryl ester association as well as time- and concentration-dependent cholesterol efflux from SR-BI overexpressing Chinese hamster ovary cells were, depending on the degree of HOCl modification of HDL, markedly impaired. The most significant findings of this study were that the presence of very low concentrations of HOCl-HDL severely impaired SR-BI-mediated bidirectional cholesterol flux mediated by native HDL. The colocalization of immunoreactive HOCl-modified epitopes with apolipoprotein A-I along with deposits of lipids in serial sections of human atheroma shown here indicates that the myeloperoxidase-H(2)O(2)-halide system contributes to oxidative damage of HDL in vivo.

Amino Acids↗

PubMed2004

Sterol regulation of scavenger receptor class B type I in macrophages.

Scavenger receptor class B type I (SR-BI) is expressed in macrophages, but its role in sterol trafficking in these cells remains controversial. We examined the effect of sterol loading on SR-BI expression in human monocytes/macrophages, mouse peritoneal macrophages, and a cultured mouse macrophage cell line (J774 cells). Sterol loading using either acetylated LDL or 25-hydroxycholesterol resulted in a time- and concentration-dependent decrease in SR-BI protein and mRNA levels. Treatment of lipid-loaded J774 cells with cyclodextrin or HDL to promote cellular sterol efflux was associated with an increase in SR-BI expression. Studies were performed to determine if the sterol-associated downregulation of SR-BI in macrophages was mediated by either sterol regulatory element binding proteins (SREBPs) or the liver X receptor (LXR). Expression of constitutively active SREBPs failed to alter the expression of a luciferase reporter placed downstream of a 2556 bp 5' flanking sequence from the mouse SR-BI gene. Reduction in SR-BI expression was also seen in sterol-loaded peritoneal macrophages from mice expressing no LXRalpha and LXRbeta. We conclude that SR-BI levels in macrophages are responsive to changes in intracellular sterol content and that these sterol-associated changes are not mediated by LXR and are unlikely to be mediated by an SREBP pathway.

Animals↗

PubMed2000

Transcriptional regulation of rat scavenger receptor class B type I gene.

The scavenger receptor class B type I (SR-BI) mediates the selective transport of lipids from high density lipoprotein to cells and plays an important role in the reverse uptake of cholesterol to the liver and in the delivery of substrates for steroidogenesis in steroidogenic organs. We report here on the isolation and characterization of the upstream promoter region of the rat SR-BI gene. The transcription start site for rat SR-BI was mapped, and DNA sequence analysis revealed the presence of binding sites for the Sp1 family in the proximal 5'-flanking region. Analysis of deletion mutants with different 5' lengths revealed that the region between -121 and -90 base pairs from the transcription start site is essential for the efficient transcription of SR-BI. Both Sp1 and Sp3 bind to three GC boxes in the region (-141 to -1 base pairs) in a sequence-specific manner. Mutations in any of the GC boxes decreased efficient transcription from this promoter in MA-10 mouse Leydig tumor cells. The overexpression of Sp1 or Sp3 protein enhanced the rat SR-BI promoter activity. These results indicate that Sp1 family members of transcription factors are essential for transcription of the rat SR-BI gene.

Animals↗

PubMed2000

Endocytic uptake of advanced glycation end products by mouse liver sinusoidal endothelial cells is mediated by a scavenger receptor distinct from the macrophage scavenger receptor class A.

Previous studies with peritoneal macrophages obtained from macrophage scavenger receptor class A (MSR-A) knock-out mice showed that the endocytic uptake of advanced glycation end products (AGE) by macrophages was mediated mainly by MSR-A. However, it is controversial whether the endocytic uptake of intravenously injected AGE proteins by liver sinusoidal endothelial cells (LECs) is similarly explained by receptor-mediated endocytosis via MSR-A. The present study was conducted to compare the capacity to endocytose AGE proteins in LECs and peritoneal macrophages obtained from MSR-A knock-out and littermate wild-type mice. The endocytic degradation capacity of MSR-A knock-out LECs for AGE-BSA was indistinguishable from that of wild-type LECs, whereas that of MSR-A knock-out peritoneal macrophages for AGE-BSA was decreased to 30% of that in wild-type cells. Similarly, the endocytic degradation of MSR-A knock-out LECs for acetylated low-density lipoprotein (acetyl-LDL) did not differ from that of wild-type LECs, whereas the endocytic degradation of acetyl-LDL by MSR-A knock-out peritoneal macrophages was less than 20% of that in wild-type cells. Furthermore, formaldehyde-treated serum albumin (f-Alb), a ligand known to undergo scavenger-receptor-mediated endocytosis by LECs, was effectively taken up by MSR-A knock-out LECs at a capacity that did not differ from that of wild-type LECs. Moreover, the endocytic uptake of AGE-BSA by LECs was effectively competed for by unlabelled f-Alb or acetyl-LDL. These results indicate that the scavenger-receptor ligands AGE proteins, acetyl-LDL and f-Alb are endocytosed by LECs through a non-MSR-A pathway.

Animals↗

PubMed2002

Scavenger receptors class A-I/II and CD36 are the principal receptors responsible for the uptake of modified low density lipoprotein leading to lipid loading in macrophages.

Modification of low density lipoprotein (LDL) can result in the avid uptake of these lipoproteins via a family of macrophage transmembrane proteins referred to as scavenger receptors (SRs). The genetic inactivation of either of two SR family members, SR-A or CD36, has been shown previously to reduce oxidized LDL uptake in vitro and atherosclerotic lesions in mice. Several other SRs are reported to bind modified LDL, but their contribution to macrophage lipid accumulation is uncertain. We generated mice lacking both SR-A and CD36 to determine their combined impact on macrophage lipid uptake and to assess the contribution of other SRs to this process. We show that SR-A and CD36 account for 75-90% of degradation of LDL modified by acetylation or oxidation. Cholesteryl ester derived from modified lipoproteins fails to accumulate in macrophages taken from the double null mice, as assessed by histochemistry and gas chromatography-mass spectrometry. These results demonstrate that SR-A and CD36 are responsible for the preponderance of modified LDL uptake in macrophages and that other scavenger receptors do not compensate for their absence.

Animals↗