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Implications of cerebrovascular ATP-binding cassette transporter G1 (ABCG1) and apolipoprotein M in cholesterol transport at the blood-brain barrier

Kober, Alexandra Carmen; Manavalan, Anil Paul Chirackal; Tam-Amersdorfer, Carmen; Holmér, Andreas LU ; Saeed, Ahmed; Fanaee-Danesh, Elham; Zandl, Martina; Albrecher, Nicole Maria; Björkhem, Ingemar and Kostner, Gerhard M., et al. (2017) In Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids 1862(6). p.573-588
Abstract

Impaired cholesterol/lipoprotein metabolism is linked to neurodegenerative diseases such as Alzheimer's disease (AD). Cerebral cholesterol homeostasis is maintained by the highly efficient blood-brain barrier (BBB) and flux of the oxysterols 24(S)-hydroxycholesterol and 27-hydroxycholesterol, potent liver-X-receptor (LXR) activators. HDL and their apolipoproteins are crucial for cerebral lipid transfer, and loss of ATP binding cassette transporters (ABC)G1 and G4 results in toxic accumulation of oxysterols in the brain. The HDL-associated apolipoprotein (apo)M is positively correlated with pre-β HDL formation in plasma; its presence and function in the brain was thus far unknown. Using an in vitro model of the BBB, we examined... (More)

Impaired cholesterol/lipoprotein metabolism is linked to neurodegenerative diseases such as Alzheimer's disease (AD). Cerebral cholesterol homeostasis is maintained by the highly efficient blood-brain barrier (BBB) and flux of the oxysterols 24(S)-hydroxycholesterol and 27-hydroxycholesterol, potent liver-X-receptor (LXR) activators. HDL and their apolipoproteins are crucial for cerebral lipid transfer, and loss of ATP binding cassette transporters (ABC)G1 and G4 results in toxic accumulation of oxysterols in the brain. The HDL-associated apolipoprotein (apo)M is positively correlated with pre-β HDL formation in plasma; its presence and function in the brain was thus far unknown. Using an in vitro model of the BBB, we examined expression, regulation, and functions of ABCG1, ABCG4, and apoM in primary porcine brain capillary endothelial cells (pBCEC). RT Q-PCR analyses and immunoblotting revealed that in addition to ABCA1 and scavenger receptor, class B, type I (SR-BI), pBCEC express high levels of ABCG1, which was up-regulated by LXR activation. Immunofluorescent staining, site-specific biotinylation and immunoprecipitation revealed that ABCG1 is localized both to early and late endosomes and on apical and basolateral plasma membranes. Using siRNA interference to silence ABCG1 (by 50%) reduced HDL-mediated [3H]-cholesterol efflux (by 50%) but did not reduce [3H]-24(S)-hydroxycholesterol efflux. In addition to apoA-I, pBCEC express and secrete apoM mainly to the basolateral (brain) compartment. HDL enhanced expression and secretion of apoM by pBCEC, apoM-enriched HDL promoted cellular cholesterol efflux more efficiently than apoM-free HDL, while apoM-silencing diminished cellular cholesterol release. We suggest that ABCG1 and apoM are centrally involved in regulation of cholesterol metabolism/turnover at the BBB.

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keywords
Cerebral cholesterol homeostasis, Endothelial cells, HDL, Liver-X receptors, Oxysterols
in
Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids
volume
1862
issue
6
pages
16 pages
publisher
Elsevier
external identifiers
  • scopus:85015837034
  • wos:000401595100001
ISSN
1388-1981
DOI
10.1016/j.bbalip.2017.03.003
language
English
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yes
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841d77d6-cd91-4ad0-8170-1a3bb75ea902
date added to LUP
2017-04-05 07:16:18
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2018-01-07 11:57:54
@article{841d77d6-cd91-4ad0-8170-1a3bb75ea902,
  abstract     = {<p>Impaired cholesterol/lipoprotein metabolism is linked to neurodegenerative diseases such as Alzheimer's disease (AD). Cerebral cholesterol homeostasis is maintained by the highly efficient blood-brain barrier (BBB) and flux of the oxysterols 24(S)-hydroxycholesterol and 27-hydroxycholesterol, potent liver-X-receptor (LXR) activators. HDL and their apolipoproteins are crucial for cerebral lipid transfer, and loss of ATP binding cassette transporters (ABC)G1 and G4 results in toxic accumulation of oxysterols in the brain. The HDL-associated apolipoprotein (apo)M is positively correlated with pre-β HDL formation in plasma; its presence and function in the brain was thus far unknown. Using an in vitro model of the BBB, we examined expression, regulation, and functions of ABCG1, ABCG4, and apoM in primary porcine brain capillary endothelial cells (pBCEC). RT Q-PCR analyses and immunoblotting revealed that in addition to ABCA1 and scavenger receptor, class B, type I (SR-BI), pBCEC express high levels of ABCG1, which was up-regulated by LXR activation. Immunofluorescent staining, site-specific biotinylation and immunoprecipitation revealed that ABCG1 is localized both to early and late endosomes and on apical and basolateral plasma membranes. Using siRNA interference to silence ABCG1 (by 50%) reduced HDL-mediated [<sup>3</sup>H]-cholesterol efflux (by 50%) but did not reduce [<sup>3</sup>H]-24(S)-hydroxycholesterol efflux. In addition to apoA-I, pBCEC express and secrete apoM mainly to the basolateral (brain) compartment. HDL enhanced expression and secretion of apoM by pBCEC, apoM-enriched HDL promoted cellular cholesterol efflux more efficiently than apoM-free HDL, while apoM-silencing diminished cellular cholesterol release. We suggest that ABCG1 and apoM are centrally involved in regulation of cholesterol metabolism/turnover at the BBB.</p>},
  author       = {Kober, Alexandra Carmen and Manavalan, Anil Paul Chirackal and Tam-Amersdorfer, Carmen and Holmér, Andreas and Saeed, Ahmed and Fanaee-Danesh, Elham and Zandl, Martina and Albrecher, Nicole Maria and Björkhem, Ingemar and Kostner, Gerhard M. and Dahlbäck, Björn and Panzenboeck, Ute},
  issn         = {1388-1981},
  keyword      = {Cerebral cholesterol homeostasis,Endothelial cells,HDL,Liver-X receptors,Oxysterols},
  language     = {eng},
  month        = {06},
  number       = {6},
  pages        = {573--588},
  publisher    = {Elsevier},
  series       = {Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids},
  title        = {Implications of cerebrovascular ATP-binding cassette transporter G1 (ABCG1) and apolipoprotein M in cholesterol transport at the blood-brain barrier},
  url          = {http://dx.doi.org/10.1016/j.bbalip.2017.03.003},
  volume       = {1862},
  year         = {2017},
}