Implications of cerebrovascular ATP-binding cassette transporter G1 (ABCG1) and apolipoprotein M in cholesterol transport at the blood-brain barrier.
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.
Institute of Pathophysiology and Immunology, Medical University of Graz, Graz, Austria.
Alexandra Carmen
AC
Kober
Institute of Pathophysiology and Immunology, Medical University of Graz, Graz, Austria.
Anil Paul Chirackal
APC
Manavalan
Institute of Pathophysiology and Immunology, Medical University of Graz, Graz, Austria.
Carmen
C
Tam-Amersdorfer
Department of Translational Medicine, University Hospital SUS, Malmö, Lund University, Sweden.
Andreas
A
Holmér
Division of Clinical Chemistry, Department of Laboratory Medicine, Karolinska University Hospital, Karolinska Institute Huddinge, Huddinge, Sweden.
Ahmed
A
Saeed
Institute of Pathophysiology and Immunology, Medical University of Graz, Graz, Austria.
Elham
E
Fanaee-Danesh
Institute of Pathophysiology and Immunology, Medical University of Graz, Graz, Austria.
Martina
M
Zandl
Institute of Pathophysiology and Immunology, Medical University of Graz, Graz, Austria.
Nicole Maria
NM
Albrecher
Division of Clinical Chemistry, Department of Laboratory Medicine, Karolinska University Hospital, Karolinska Institute Huddinge, Huddinge, Sweden.
Ingemar
I
Björkhem
Institute of Molecular Biology and Biochemistry, Medical University of Graz, Graz, Austria.
Gerhard M
GM
Kostner
Department of Translational Medicine, University Hospital SUS, Malmö, Lund University, Sweden.
Björn
B
Dahlbäck
Institute of Pathophysiology and Immunology, Medical University of Graz, Graz, Austria. Electronic address: ute.panzenboeck@medunigraz.at.
Ute
U
Panzenboeck
D064286:ATP Binding Cassette Transporter 1 / Q000378:metabolism; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1 / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001053:Apolipoproteins / Q000235:genetics / Q000378:metabolism*; D001693:Biological Transport, Active / Q000502:physiology; D001812:Blood-Brain Barrier / Q000378:metabolism*; D002462:Cell Membrane / Q000235:genetics / Q000378:metabolism*; D002784:Cholesterol / Q000235:genetics / Q000378:metabolism*; D000071518:Liver X Receptors / Q000235:genetics / Q000378:metabolism; D008954:Models, Biological; D013552:Swine
D064286:ATP Binding Cassette Transporter 1; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D001053:Apolipoproteins; D000071518:Liver X Receptors; D002784:Cholesterol
Cerebral cholesterol homeostasis; Endothelial cells; HDL; Liver-X receptors; Oxysterols