Abnormal lipoprotein metabolism and reversible female infertility in HDL receptor (SR-BI)–deficient mice

Miettinen, Helena E.; Rayburn, Helen; Krieger, Monty

doi:10.1172/jci200113288

Cited by 44 publications

(49 citation statements)

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“…J20 male mice were mated with SR-BI +/− female mice. We used heterozygous mice, as SR-BI female homozygous mutant mice are sterile (13). Probucol has been shown to reverse the infertility problems of SR-BI mutant mice (13), nevertheless we decided not to use it as it has been shown to increase ApoE levels in the brain (23) that could possibly affect the phenotype of the mice.…”

Section: Resultsmentioning

confidence: 99%

“…Scavenger receptor class B type I (SR-BI) has been identified as a high-density lipoprotein (HDL) receptor that mediates cholesterol transport (11). SR-BI has been detected in mouse brain (12), and SR-BI gene deletion in mice results in elevated HDL cholesterol and female sterility (5,13). SR-BI and ATP-binding cassette transporter-1 (ABCA1) play a major role in "reverse cholesterol transport," the HDL-mediated transport of cholesterol from the periphery to the liver (14).…”

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confidence: 99%

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Scavenger receptor class B type I (SR-BI) regulates perivascular macrophages and modifies amyloid pathology in an Alzheimer mouse model

Thanopoulou

Fragkouli

Stylianopoulou

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

128

114

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Scavenger receptor class B type I (SR-BI) is a high-density lipoprotein receptor that regulates cholesterol efflux from the peripheral tissues to the liver. SR-BI has been identified on astrocytes and vascular smooth muscle cells in Alzheimer's disease brain and has been shown to mediate adhesion of microglia to fibrillar amyloid-β (Aβ). Here we report that SR-BI mediates perivascular macrophage response and regulates Aβ-related pathology and cerebral amyloid angiopathy in an Alzheimer's mouse model. Reduction or deletion of SR-BI gene in heterozygous or homozygous deficient mice (SR-BI +/− , −/− ) resulted in a significant increase in perivascular macrophages in the brain. SR-BI deletion had no effect on apolipoprotein E or apolipoprotein AI levels in the mouse brain. Our analysis revealed increased levels of SR-BI expression in the brains of human amyloid precursor protein (Swedish, Indiana) transgenic mice (J20 line). To evaluate the role of SR-BI in Alzheimer's disease pathogenesis, we inactivated one SR-BI allele in J20 transgenic mice. SR-BI reduction in J20/SR-BI +/− mice enhanced fibrillar amyloid deposition and cerebral amyloid angiopathy and also exacerbated learning and memory deficits compared with J20 littermates. Immunohistochemical analysis revealed localization of SR-BI on perivascular macrophages in tight association with Aβ deposits. Our data suggest that SR-BI reduction impairs the response of perivascular macrophages to Aβ and enhances the Aβ-related phenotype and cerebral amyloid angiopathy in J20 mice. These results reveal that SR-BI, a scavenger receptor primarily involved in high-density lipoprotein cholesterol transport, plays an essential role in Alzheimer's disease and cerebral amyloid angiopathy.high-density lipoprotein receptor | dementia

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Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

Scavenger receptor class B type I (SR-BI) regulates perivascular macrophages and modifies amyloid pathology in an Alzheimer mouse model

Thanopoulou

Fragkouli

Stylianopoulou

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

128

114

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“…Experiments with SR-BI-deficient or SR-BI-overexpressing mice have provided important insights into SR-BI function and potential roles of SR-BI and HDL metabolism in pathophysiology, including female infertility, aberrant red blood cell development, and cardiovascular disease (6,7,10,15). BLTs and other small molecules isolated by using the approach described here may prove helpful in further studying the physiology of these systems.…”

Section: Discussionmentioning

confidence: 99%

“…Studies in mice have shown that alterations in SR-BI expression can profoundly influence several physiologic systems, including those involved in biliary cholesterol secretion, female fertility, red blood cell development, atherosclerosis, and the development of coronary heart disease (3)(4)(5)(6)(7)(8)(9)(10)(11). SR-BI controls HDL metabolism by mediating the cellular selective uptake of cholesteryl esters and other lipids from plasma HDL (1,2).…”

mentioning

confidence: 99%

Discovery of chemical inhibitors of the selective transfer of lipids mediated by the HDL receptor SR-BI

Nieland

Penman

Dori

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

193

234

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The high-density lipoprotein (HDL) receptor, scavenger receptor, class B, type I (SR-BI), mediates both the selective uptake of lipids, mainly cholesterol esters, from HDL to cells and the efflux of cholesterol from cells to lipoproteins. The mechanism underlying these lipid transfers is distinct from classic receptor-mediated endocytosis, but it remains poorly understood. To investigate SR-BI's mechanism of action and in vivo function, we developed a high-throughput screen to identify small molecule inhibitors of SR-BI-mediated lipid transfer in intact cells. We identified five compounds that in the low nanomolar to micromolar range block lipid transport (BLTs), both selective uptake and efflux. The effects of these compounds were highly specific to the SR-BI pathway, because they didn't interfere with receptor-mediated endocytosis or with other forms of intracellular vesicular traffic. Surprisingly, all five BLTs enhanced, rather than inhibited, HDL binding by increasing SR-BI's binding affinity for HDL (decreased dissociation rates). Thus, the BLTs provide strong evidence for a mechanistic coupling between HDL binding and lipid transport and may serve as a starting point for the development of pharmacologically useful modifiers of SR-BI activity and, thus, HDL metabolism.

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“…Different lines of evidence are of support that SR-BI is a physiologically relevant HDL receptor, studies which are primarily addressing its role in cholesterol metabolism [12,13]. Further studies demonstrated that SR-BI-deficiency in rodents leads to defective erythroid maturation and abnormalities in the female reproductive system [13,60]. Evidence is accumulating that cholesterol must be considered as an essential agent in embryonic development.…”

Section: Discussionmentioning

confidence: 99%

Trophoblast‐like human choriocarcinoma cells serve as a suitable in vitro model for selective cholesteryl ester uptake from high density lipoproteins

Wadsack¹,

Hrzenjak²,

Hammer³

et al. 2003

European Journal of Biochemistry

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As human choriocarcinoma cells display many of the biochemical and morphological characteristics reported for in utero invasive trophoblast cells we have studied cholesterol supply from high density lipoproteins (HDL) to these cells. Binding properties of 125I‐labeled HDL subclass 3 (HDL3) at 4 °C were similar for BeWo, JAr, and Jeg3 choriocarcinoma cell lines while degradation rates at 37 °C were highest for BeWo. Calculating the selective cholesteryl ester (CE)‐uptake as the difference between specific cell association of [3H]CE‐labeled HDL3 and holoparticle association of 125I‐labeled HDL3 revealed that in BeWo cells, the selective CE‐uptake was slightly lower than holoparticle association. However, the pronounced capacity for specific cell association of [3H]CE‐HDL3 and selective [3H]CE‐uptake in excess of HDL3–holoparticle association, and cAMP–mediated enhanced cell association of [3H]CE‐HDL3 in JAr and Jeg3 suggested the scavenger receptor class B, type I (SR‐BI) to be responsible for this pathway. Abundant expression of SR‐BI (but not SR‐BII, a splice variant of SR‐BI) could be observed in JAr and Jeg3 but not in BeWo cells using RT‐PCR, Northern and Western blot analysis, and immunocytochemical technique. Adenovirus‐mediated overexpression of SR‐BI in all three choriocarcinoma cell lines resulted in an enhanced capacity for cell association of [3H]CE‐HDL3 (20‐fold in BeWo; fivefold in JAr and Jeg3). The fact that exogenous HDL3 remarkably increases proliferation in JAr and Jeg3 supports the notion that selective CE‐uptake and subsequent intracellular generation of cholesterol is coupled to cellular growth. From our findings we propose that JAr and Jeg3 cells serve as a suitable in vitro model to study selective CE‐supply to human placental cells.

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Abnormal lipoprotein metabolism and reversible female infertility in HDL receptor (SR-BI)–deficient mice

Cited by 44 publications

References 46 publications

Scavenger receptor class B type I (SR-BI) regulates perivascular macrophages and modifies amyloid pathology in an Alzheimer mouse model

Scavenger receptor class B type I (SR-BI) regulates perivascular macrophages and modifies amyloid pathology in an Alzheimer mouse model

Discovery of chemical inhibitors of the selective transfer of lipids mediated by the HDL receptor SR-BI

Trophoblast‐like human choriocarcinoma cells serve as a suitable in vitro model for selective cholesteryl ester uptake from high density lipoproteins

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