ABCA1 and Scavenger Receptor Class B, Type I, Are Modulators of Reverse Sterol Transport at an in Vitro Blood-Brain Barrier Constituted of Porcine Brain Capillary Endothelial Cells

Panzenboeck, Ute; Balázs, Zoltán; Sovic, Andrea; Hrzenjak, Andelko; Levak-Frank, Sanja; Wintersperger, Andrea; Malle, Ernst; Sattler, Wolfgang

doi:10.1074/jbc.m207601200

Cited by 182 publications

(162 citation statements)

References 55 publications

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“…In addition, feeding of 0.5% d6-cholesterol to mice and rats for 10 days resulted in cerebral accumulation of less than 1% in either species ( 46 ). An in vitro porcine brain endothelial cell monolayer Transwell setup revealed an approximately 2% apical fl ux of cholesterol after basolateral administration ( 47 ). In our experiments, the basolateral uptake of plant sterols and cholesterol over 24 h was very limited (campesterol: 0.26%, sitosterol: 0.21%, and cholesterol: 3.68% compared with the common 52% uptake at the apical side; data not shown).…”

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confidence: 99%

Dietary intake of plant sterols stably increases plant sterol levels in the murine brain

Vanmierlo

Weingärtner

Pol

et al. 2012

Journal of Lipid Research

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This article is available online at http://www.jlr.org stigmasterol (ethyl group at C24, ⌬ 22) ( 1, 2 ). In contrast to cholesterol, these sterols are exclusively derived from the diet and cannot be synthesized endogenously in mammals. A high plant sterol intake (2-2.5 g/day) leads to reduced total and LDL-cholesterol ( ‫ف‬ 12%) in the circulation ( 3, 4 ). Therefore, plant sterols are frequently applied as functional, nonprescription food additives to prevent atherosclerosis and cardiovascular diseases ( 5 ). However, administration of high-dose plant sterols results in increased serum plant sterol concentrations ( 6 ). Hard end-point studies showing an effect on the number of cardiovascular events or on mortality after long-term intake of high-dose plant sterols are lacking ( 7 ), as are insights into the underlying molecular mechanisms ( 8 ). Because adverse events upon plant sterol administration in animal studies are increasingly being reported to cause adverse events ( 9 ), it is a current topic of debate ( 10 ).In contrast to peripheral tissues, all cholesterol within the central nervous system is synthesized in situ because circulating cholesterol is not able to cross the blood-brain barrier (BBB) ( 11,12 ). Recently, we reported that circulating plant sterols, in contrast to cholesterol, can enter the brains of ATP binding cassette g5 (Abcg5)-defi cient mice, a model for phytosterolemia ( 13 ). ABCG5 and ABCG8 act as functional heterodimer transporters at the apical membranes of enterocytes and hepatocytes, where they excrete plant sterols into the intestinal lumen and bile, Abstract Plant sterols such as sitosterol and campesterol are frequently administered as cholesterol-lowering supplements in food. Recently, it has been shown in mice that, in contrast to the structurally related cholesterol, circulating plant sterols can enter the brain. We questioned whether the accumulation of plant sterols in murine brain is reversible. After being fed a plant sterol ester-enriched diet for 6 weeks, C57BL/6NCrl mice displayed signifi cantly increased concentrations of plant sterols in serum, liver, and brain by 2-to 3-fold. Blocking intestinal sterol uptake for the next 6 months while feeding the mice with a plant stanol ester -enriched diet resulted in strongly decreased plant sterol levels in serum and liver, without affecting brain plant sterol levels. Relative to plasma concentrations, brain levels of campesterol were higher than sitosterol, suggesting that campesterol traverses the blood-brain barrier more effi ciently. In vitro experiments with brain endothelial cell cultures showed that campesterol crossed the blood-brain barrier more effi ciently than sitosterol. We conclude that, over a 6-month period, plant sterol accumulation in murine brain is virtually irreversible. Plant sterols differ structurally from cholesterol by an additional methyl or ethyl group at C24 and/or a double bond at C22 ( ⌬ 22). The most prevalent plant sterols are campesterol (methyl group at C24), sitosterol (ethyl group at C24)...

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confidence: 99%

Dietary intake of plant sterols stably increases plant sterol levels in the murine brain

Vanmierlo

Weingärtner

Pol

et al. 2012

Journal of Lipid Research

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“…It was recently demonstrated that primary porcine brain capillary endothelial cells express mRNA and protein of the cholesterol transporter ABCA1. 21 It was also shown that along with ABCA1 expression, the oxysterol 24S-hydroxycholesterol enhanced apoA1-dependent efflux of cholesterol from cultured brain endothelial cells. Based on results of experiments with an in vitro model system, the possibility was discussed that the ABCA1 transporter and the scavenger receptor SR-B1 may be involved in an autoregulatory mechanism for "backflush" of cholesterol to the brain.…”

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confidence: 99%

Brain Cholesterol: Long Secret Life Behind a Barrier

Björkhem

Meaney

2004

ATVB

855

732

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Abstract-Although an immense knowledge has accumulated concerning regulation of cholesterol homeostasis in the body, this does not include the brain, where details are just emerging. Approximately 25% of the total amount of the cholesterol present in humans is localized to this organ, most of it present in myelin. Almost all brain cholesterol is a product of local synthesis, with the blood-brain barrier efficiently protecting it from exchange with lipoprotein cholesterol in the circulation. Thus, there is a highly efficient apolipoprotein-dependent recycling of cholesterol in the brain, with minimal losses to the circulation. Under steady-state conditions, most of the de novo synthesis of cholesterol in the brain appears to be balanced by excretion of the cytochrome P-450 -generated oxysterol 24S-hydroxycholesterol. This oxysterol is capable of escaping the recycling mechanism and traversing the blood-brain barrier. Cholesterol levels and cholesterol turnover are affected in neurodegenerating disorders, and the capacity for cholesterol transport and recycling in the brain seems to be of importance for the development of such diseases. The possibility has been discussed that administration of inhibitors of cholesterol synthesis may reduce the prevalence of Alzheimer disease. No firm conclusions can, however, be drawn from the studies presented thus far.In the present review, the most recent advances in our understanding of cholesterol turnover in the brain is discussed. Key Words: brain cholesterol Ⅲ blood-brain barrier Ⅲ cholesterol 24S-hydroxylase Ⅲ Alzheimer disease Ⅲ statins H ighly sophisticated regulatory systems have evolved for the maintenance of cholesterol homeostasis in the body. There is a distinct difference between the situation in the central nervous system and that in most other extrahepatic tissues. Outside the brain, the cellular needs for cholesterol is covered by de novo synthesis and by cellular uptake of lipoprotein cholesterol from the circulation. In the brain, the blood-brain barrier effectively prevents uptake from the circulation, and de novo synthesis is responsible for practically all cholesterol present in this organ. The independence of the isolated pool of cholesterol in the brain is likely to reflect a high need for constancy in the cholesterol content of membrane and myelin, a constancy that would be difficult to keep if brain cholesterol had been exchangeable with lipoprotein cholesterol.The importance of cholesterol in the nervous system was recognized as early as 1834, when Couerbe's observations lead him to regard cholesterol as un element principal of the nervous system. 1 Despite concerted efforts in the interim, it is only during the past few decades that the brain has begun to surrender the secrets of the behavior of one of its most abundant lipids.In the present brief review, we summarize the basal characteristics of brain cholesterol and some recent findings with respect to homeostasis of this compound in the brain. Emphasis is put on the newly described relation betwee...

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“…Almost all of the central nervous system cholesterol is derived from in situ biosynthesis and is transported by lipoproteins similar to plasma HDL (13). The main apolipoproteins are apoE, produced by astrocytes (14) and microglia (15), and apoA-I from the systemic circulation or from brain endothelial cells (16). Mutations that affect the synthesis and intracellular traffic of cholesterol in neurons lead to neurodegeneration like that is seen in Smith-Lemli-Opitz syndrome (17) and NiemannPick type C disease (18), and disturbances in brain cholesterol metabolism may contribute to the pathogenesis of Alzheimer's disease (AD) (19).…”

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confidence: 99%

22R-Hydroxycholesterol and 9-cis-Retinoic Acid Induce ATP-binding Cassette Transporter A1 Expression and Cholesterol Efflux in Brain Cells and Decrease Amyloid β Secretion

Koldamova

Lefterov

Ikonomović

et al. 2003

Journal of Biological Chemistry

224

209

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The ATP-binding cassette transporter A1 (ABCA1) is a major regulator of peripheral cholesterol efflux and plasma high density lipoprotein metabolism. In adult rat brain we found high expression of ABCA1 in neurons in the hypothalamus, thalamus, amygdala, cholinergic basal forebrain, and hippocampus. Large neurons of the cholinergic nucleus basalis together with CA1 and CA3 pyramidal neurons were among the most abundantly immunolabeled neurons. Glia cells were largely negative. Because cholesterol homeostasis may have an essential role in central nervous system function and neurodegeneration, we examined ABCA1 expression and function in different brain cell types using cultures of primary neurons, astrocytes, and microglia isolated from embryonic rat brain. The basal ABCA1 mRNA and protein levels detected in these cell types were increased markedly after exposure to oxysterols and 9-cis-retinoic acid, which are ligands for the nuclear hormone liver X receptors and retinoic X receptors, respectively. Functionally, the increased ABCA1 expression caused by these ligands was followed by elevated apoA-I-and apoE-specific cholesterol efflux in neurons and glia. In non-neuronal and neuronal cells overexpressing a human Swedish variant of amyloid precursor protein, 22R-hydroxycholesterol and 9-cis-retinoic acid induced ABCA1 expression and increased apoA-I-mediated cholesterol efflux consequently decreasing cellular cholesterol content. More importantly, we demonstrated that these ligands alone or in combination with apoA-I caused a substantial reduction in the stability of amyloid precursor protein C-terminal fragments and decreased amyloid ␤ production. These effects of 22R-hydroxycholesterol may provide a novel strategy to decrease amyloid ␤ secretion and consequently reduce the amyloid burden in the brain.

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ABCA1 and Scavenger Receptor Class B, Type I, Are Modulators of Reverse Sterol Transport at an in Vitro Blood-Brain Barrier Constituted of Porcine Brain Capillary Endothelial Cells

Cited by 182 publications

References 55 publications

Dietary intake of plant sterols stably increases plant sterol levels in the murine brain

Dietary intake of plant sterols stably increases plant sterol levels in the murine brain

Brain Cholesterol: Long Secret Life Behind a Barrier

22R-Hydroxycholesterol and 9-cis-Retinoic Acid Induce ATP-binding Cassette Transporter A1 Expression and Cholesterol Efflux in Brain Cells and Decrease Amyloid β Secretion

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