Isoform-Dependent Cholesterol Efflux From Macrophages by Apolipoprotein E Is Modulated by Cell Surface Proteoglycans

Hara, Mariko; Matsushima, Teruhiko; Satoh, Hiroaki; Iso-O, Naoyuki; Noto, Hiroshi; Togo, Masami; Kimura, Satoshi; Hashimoto, Yoshiaki; Tsukamoto, Kazuhisa

doi:10.1161/01.atv.0000054199.78458.4b

Cited by 42 publications

(35 citation statements)

References 41 publications

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“…Because cellassociated apoE represented 1.3 Ϯ 0.1% of total apoE secreted into the media, it is highly unlikely that preferential retention of apoE4 accounts for the differences in secreted apoE levels. Moreover, treating CCF-STTG1 cells with heparinase to release the cell surface bound apoE (Hara et al 2003) increased the total amount of both apoE3 and apoE4 secreted into the media over a 24 h period, but it did not significantly alter the ratio of apoE4 to apoE3 (supplemental Fig. S1, available at www.jneurosci.org as supplemental material).…”

Section: Resultsmentioning

confidence: 99%

Impact of Apolipoprotein E (ApoE) Polymorphism on Brain ApoE Levels

Riddell¹,

Zhou²,

Atchison³

et al. 2008

J. Neurosci.

293

246

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Inheritance of the apoE4 allele (4) increases the risk of developing Alzheimer's disease; however, the mechanisms underlying this association remain elusive. Recent data suggest that inheritance of 4 may lead to reduced apoE protein levels in the CNS. We therefore examined apoE protein levels in the brains, CSF and plasma of 2/2, 3/3, and 4/4 targeted replacement mice. These apoE mice showed a genotype-dependent decrease in apoE levels; 2/2 Ͼ3/3 Ͼ4/4. Next, we sought to examine the relative contributions of apoE4 and apoE3 in the 3/4 mouse brains. ApoE4 represented 30 -40% of the total apoE. Moreover, the absolute amount of apoE3 per allele was similar between 3/3 and 3/4 mice, implying that the reduced levels of total apoE in 3/4 mice can be explained by the reduction in apoE4 levels. In culture medium from 3/4 human astrocytoma or 3/3, 4/4 and 3/4 primary astrocytes, apoE4 levels were consistently lower than apoE3. Secreted cholesterol levels were also lower from 4/4 astrocytes. Pulse-chase experiments showed an enhanced degradation and reduced half-life of newly synthesized apoE4 compared with apoE3. Together, these data suggest that astrocytes preferentially degrade apoE4, leading to reduced apoE4 secretion and ultimately to reduced brain apoE levels. Moreover, the genotype-dependent decrease in CNS apoE levels, mirror the relative risk of developing AD, and suggest that low levels of total apoE exhibited by 4 carriers may directly contribute to the disease progression, perhaps by reducing the capacity of apoE to promote synaptic repair and/or A␤ clearance.

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Section: Resultsmentioning

confidence: 99%

Impact of Apolipoprotein E (ApoE) Polymorphism on Brain ApoE Levels

Riddell¹,

Zhou²,

Atchison³

et al. 2008

J. Neurosci.

293

246

View full text Add to dashboard Cite

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“…In this study we demonstrated that cholesterol efflux is the key property of apoE to promote intracellular A␤ degradation. Since the cholesterol efflux activity is apoE isoform-dependent (E2 Ͼ E3 Ͼ E4) (76,77), the higher risk of AD observed in the apoE4 carriers may be due to the poorer efficiency of cholesterol efflux by apoE4. Cellular cholesterol levels governed by the activity of apoE isoforms may directly regulate A␤ degradation (8).…”

Section: Discussionmentioning

confidence: 99%

Apolipoprotein E Promotes β-Amyloid Trafficking and Degradation by Modulating Microglial Cholesterol Levels

Lee

Tse

Smith

et al. 2012

Journal of Biological Chemistry

141

125

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Background: Intracellular A␤ degradation is enhanced in the presence of apoE. Results: Lowering cellular cholesterol levels facilitates intracellular trafficking of A␤ to lysosomes and enhances its degradation. Conversely, increasing cholesterol levels retards the delivery and inhibits degradation of A␤. Conclusion:The cholesterol efflux function of apoE mediates its ability to promote A␤ degradation. Significance: We demonstrate a direct role for cholesterol in AD.

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“…Human expression of the apoE2 and E4 isoforms has been associated with important human diseases (15)(16)(17). Isoform-specifi c effects on cellular-differentiated function have been established for neurons and macrophages (20)(21)(22)(23)(24)(25)(26), and . TG turnover in apoE isoform knock-in adipocytes.…”

Section: Discussionmentioning

confidence: 99%

“…TG hydrolysis was estimated by measuring the release of glycerol into incubation medium over 2 h ( 6 ). cell function, have been described in macrophages (20)(21)(22)(23) and neuronal cells (24)(25)(26). For example, in macrophages, the secretion of apoE2 is impaired, and there is an associated alteration in macrophage sterol effl ux mediated by apoE2.…”

Section: Adipocyte Tg Synthesis and Hydrolysismentioning

confidence: 99%

Expression of the human apoE2 isoform in adipocytes: altered cellular processing and impaired adipocyte lipogenesis

Huang

Maeda

Mazzone

2011

Journal of Lipid Research

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which adipose tissue infl uences organismal substrate distribution and metabolism in both physiological and pathophysiological states. Recently, the unexpected observation was made that the endogenous expression of apoE in adipose tissue and adipocytes importantly infl uences adipocyte differentiated function. Adipocytes that do not express endogenous apoE are smaller, contain less lipid, display a defect in lipogenesis and substrate acquisition from extracellular lipoproteins, and have alterations in the expression of genes controlling adipocyte lipid turnover ( 4-7 ). Moreover, these defects cannot be corrected by the provision of extracellular apoE in vitro or in vivo, but can be corrected by adenoviral-mediated expression of endogenous apoE in adipocytes ( 4, 5 ). Because of these effects on adipose tissue metabolism, endogenous adipocyte apoE also importantly infl uences the systemic distribution of substrate in intact animals ( 5 ). A physiological role for endogenous adipocyte apoE expression in the regulation of organismal metabolism is further underscored by the recent demonstration of physiologically relevant pathways for regulating adipocyte apoE expression (8)(9)(10)(11)(12)(13)(14).In humans, apoE is a polymorphic protein, and three common isoforms have been identifi ed: apoE2 (Cys ). The apoE3 isoform is by far the most common and is present in more than 75% of individuals. The presence of the apoE2 or apoE4 isoform has been associated with important human diseases and alterations in systemic lipoprotein metabolism ( 15-17 ). There are also observations in human populations suggesting a relationship between apoE isoform expression and adiposity, and a relationship between adiposity and lipid metabolism ( 18,19 ). In addition, important differences in cellular turnover of the apoE isoforms, with related implications for differentiated Abstract Expression of apoE in adipocytes has been shown to have an important role in modulating adipocyte triglyceride (TG) metabolism and gene expression that is independent of circulating and extracellular apoE. The impact of adipocyte expression of common human apoE isoforms was evaluated using adipocytes harvested from human apoE2, -3, and -4 knock-in mice. Expression of the apoE2 isoform was associated with an increase in adipocyte apoE gene expression and apoE synthesis. Newly synthesized apoE2 was unstable in adipocytes and demonstrated increased degradation and decreased secretion. ApoE2-expressing mice were hyperlipidemic, and had increased size of gonadal fat pads and of adipocytes, compared with apoE3 mice. In isolated cells, however, expression of the apoE2 isoform produced defective lipogenesis and increased TG hydrolysis. Incubation of adipose tissue with apoE3-containing TG-rich lipoproteins resulted in a signifi cant increase in TG in adipose tissue from apoE3 and -E4 mice, but not apoE2 mice. Reduced capacity to internalize FFA as lipogenic substrate contributed to defective lipogenesis. Newly synthesized apoE2 is unstable in adipocytes and results in...

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Isoform-Dependent Cholesterol Efflux From Macrophages by Apolipoprotein E Is Modulated by Cell Surface Proteoglycans

Cited by 42 publications

References 41 publications

Impact of Apolipoprotein E (ApoE) Polymorphism on Brain ApoE Levels

Impact of Apolipoprotein E (ApoE) Polymorphism on Brain ApoE Levels

Apolipoprotein E Promotes β-Amyloid Trafficking and Degradation by Modulating Microglial Cholesterol Levels

Expression of the human apoE2 isoform in adipocytes: altered cellular processing and impaired adipocyte lipogenesis

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