Expression of Apolipoprotein A‐I in Porcine Brain Endothelium In Vitro

Möckel, Babette; Zinke, Holger; Flach, Regina; Weiß, Birgit; Weiler-Güttler, Hartmut; Gassen, Hans Günter

doi:10.1046/j.1471-4159.1994.62020788.x

Cited by 67 publications

(42 citation statements)

References 29 publications

(40 reference statements)

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“…ApoA-I is present in brain and in cerebrospinal fluid and has been detected in senile plaques in AD patients (58,59). So far apoA-I synthesis within the brain has only been ascribed to endothelial cells of the blood brain barrier (60). It remains to be established why 24(S)-hydroxycholesterol does not alone, but only in concert with apoE or apoAI increase cholesterol efflux from astrocytes.…”

Section: Discussionmentioning

confidence: 99%

24(S)-Hydroxycholesterol Participates in a Liver X Receptor-controlled Pathway in Astrocytes That Regulates Apolipoprotein E-mediated Cholesterol Efflux

Abildayeva

Jansen

Hirsch‐Reinshagen

et al. 2006

Journal of Biological Chemistry

216

188

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Both apolipoprotein E (apoE) and 24(S)-hydroxycholesterol are involved in the pathogenesis of Alzheimer disease (AD). It has beenhypothesized that apoE affects AD development via isoform-specific effects on lipid trafficking between astrocytes and neurons. However, the regulation of the cholesterol supply of neurons via apoE-containing high density lipoproteins remains to be clarified. We show for the first time that the brain-specific metabolite of cholesterol produced by neurons, i.e. 24(S)-hydroxycholesterol, induces apoE transcription, protein synthesis, and secretion in a dose-and time-dependent manner in cells of astrocytic but not of neuronal origin. Moreover, 24(S)-hydroxycholesterol primes astrocytoma, but not neuroblastoma cells, to mediate cholesterol efflux to apoE. Similar results were obtained using the synthetic liver X receptor (LXR) agonist GW683965A, suggesting involvement of an LXR-controlled signaling pathway. A 10 -20-fold higher basal LXR␣ and -␤ expression level in astrocytoma compared with neuroblastoma cells may underlie these differential effects. Furthermore, apoE-mediated cholesterol efflux from astrocytoma cells may be controlled by the ATP binding cassette transporters ABCA1 and ABCG1, since their expression was also up-regulated by both compounds. In contrast, ABCG4 seems not to be involved, because its expression was induced only in neuronal cells. The expression of sterol regulatory element-binding protein (SREBP-2), low density lipoprotein receptor, 3-hydroxy-3-methylglutaryl-CoA reductase, and SREBP-1c was transiently up-regulated by GW683965A in astrocytes but down-regulated by 24(S)-hydroxycholesterol, suggesting that cholesterol efflux and synthesis are regulated independently. In conclusion, evidence is provided that 24(S)-hydroxycholesterol induces apoE-mediated efflux of cholesterol in astrocytes via an LXR-controlled pathway, which may be relevant for chronic and acute neurological diseases.

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Section: Discussionmentioning

confidence: 99%

24(S)-Hydroxycholesterol Participates in a Liver X Receptor-controlled Pathway in Astrocytes That Regulates Apolipoprotein E-mediated Cholesterol Efflux

Abildayeva

Jansen

Hirsch‐Reinshagen

et al. 2006

Journal of Biological Chemistry

216

188

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“…3B ). Unlike brain capillary EC, which are able to express and secrete apoA-I ( 35,36 ), the expression of apoA-I in EC from other sites was undetectable, which could account for the dependence of EC for nascent HDL produced by the liver and intestine to act as an acceptor for cholesterol effl ux stimulated by ABCA1 in EC. Endothelial expression of hABCA1 transgene was also unable to affect the level of plasma HDL-C in apoE-defi cient mice ( Table 2 ).…”

Section: Effect Of Hfhc Diet On Expression Of Habca1 and Endogenous Gmentioning

confidence: 96%

“…2D ). We also examined the level of apoA-I gene expression in isolated lung EC, peritoneal macrophages, and aorta, because apoA-I has been reported to be produced by endothelial cells lining the blood-brain barrier ( 35,36 ), but only trace amounts of apoA-I mRNA were detected in these tissues and cells (data not shown).…”

Section: Expression Of Habca1 Transgene and Endogenous Genesmentioning

confidence: 99%

Endothelial expression of human ABCA1 in mice increases plasma HDL cholesterol and reduces diet-induced atherosclerosis

Vaisman

Demosky

Stonik

et al. 2012

Journal of Lipid Research

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“…HDL is a lipoprotein found exclusively in cerebrospinal fluid that contains mainly apolipoprotein E (apoE) and apoA-I (7). Although apoA-I is not synthesized by neural cells, and its origin is uncertain (8,9), apoE is known to be synthesized, at least in astrocytes and microglias, to generate apoE-HDL (10,11). Many reports suggest that apoE-HDL is a key lipoprotein in the delivery of cholesterol to the neural cells, and this lipoprotein seems to increase in the lesions of injury of brain and nerves (12)(13)(14)(15)(16)(17)(18)(19)(20)(21).…”

mentioning

confidence: 99%

Mechanism for FGF-1 to regulate biogenesis of apoE-HDL in astrocytes

Ito

Nagayasu

Okumura-Noji

et al. 2007

Journal of Lipid Research

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Fibroblast growth factor-1 (FGF-1) is secreted by astrocytes and stimulates apolipoprotein E (apoE)-HDL biogenesis by an autocrine mechanism to help in recovery from brain injury. In apoE-deficient mouse astrocytes, FGF-1 stimulated cholesterol biosynthesis without enhancing its release, indicating a signaling pathway independent of apoE biosynthesis upregulation. SU5402, an inhibitor of FGF receptor, inhibited FGF-1-induced phosphorylation of MEK, ERK, and Akt, as well as all the apoE-HDL biogenesis-related events in rat astrocytes. LY294002, an inhibitor of phosphatidylinositide 3-OH kinase (PI3K) and of Akt phosphorylation, inhibited apoE-HDL secretion but not cholesterol biosynthesis, whereas U0126, an inhibitor of MEK and of ERK phosphorylation, inhibited cholesterol biosynthesis but not apoE-HDL secretion. Increase of apoE-mRNA by FGF-1 was not influenced by either inhibitor. When rat apoE/pcDNA3. his was transfected to transformed rat astrocyte GA-1 cells that otherwise do not synthesize apoE (GA-1/25), FGF-1 did not influence apoE-mRNA, but did increase the apoE secretion and Akt phosphorylation that were suppressed by LY294002. Lipid biosynthesis was increased by FGF-1 in GA-1/25 cells and suppressed by U0126. FGF-1 upregulates apoE-HDL biogenesis by three independent signaling pathways. The PI3K/Akt pathway upregulates secretion of apoE/apoE-HDL, the MEK/ERK pathway stimulates cholesterol biosynthesis, and an unknown pathway enhances apoE transcription.-Ito, J-i., Y. Nagayasu, K. Okumura-Noji, R. Lu, T. Nishida, Y. Miura, K. Asai, A. Kheirollah, S. Nakaya, and S. Yokoyama. Mechanism for FGF-1 to regulate biogenesis of apoE-HDL in astrocytes. J. Lipid Res. 2007Res. . 48: 2020Res. -2027. Supplementary key words astrocytesNeuronal cells in the central nervous system (CNS), such as neurons, oligodendroglias, and astrocytes, all appear in unique shapes, with large cell surfaces, and accordingly contain large amounts of cholesterol. Cholesterol content in the CNS could thus account for 25-30% of total body cholesterol in humans (1, 2). Cholesterol plays many key roles in the CNS, including roles in neurite outgrowth (3, 4) and synapse formation (5).Cholesterol homeostasis in animals is maintained by intra-and extracellular regulation of its metabolism (6), and extracellular transport of cholesterol in vertebrates is carried by the plasma lipoprotein system. However, the blood-brain barrier prevents the CNS from accessing this system, so the CNS operates as a unique and independent CNS-specific lipoprotein system for extracellular cholesterol transport. HDL is a lipoprotein found exclusively in cerebrospinal fluid that contains mainly apolipoprotein E (apoE) and apoA-I (7). Although apoA-I is not synthesized by neural cells, and its origin is uncertain (8, 9), apoE is known to be synthesized, at least in astrocytes and microglias, to generate apoE-HDL (10, 11). Many reports suggest that apoE-HDL is a key lipoprotein in the delivery of cholesterol to the neural cells, and this lipoprotein seems to ...

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Expression of Apolipoprotein A‐I in Porcine Brain Endothelium In Vitro

Cited by 67 publications

References 29 publications

24(S)-Hydroxycholesterol Participates in a Liver X Receptor-controlled Pathway in Astrocytes That Regulates Apolipoprotein E-mediated Cholesterol Efflux

24(S)-Hydroxycholesterol Participates in a Liver X Receptor-controlled Pathway in Astrocytes That Regulates Apolipoprotein E-mediated Cholesterol Efflux

Endothelial expression of human ABCA1 in mice increases plasma HDL cholesterol and reduces diet-induced atherosclerosis

Mechanism for FGF-1 to regulate biogenesis of apoE-HDL in astrocytes

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