title: Phospholipid transfer protein is expressed in cerebrovascular endothelial cells and involved in high density lipoprotein biogenesis and remodeling at the blood-brain barrier.
abstract: Phospholipid transfer protein (PLTP) is a key protein involved in biogenesis and remodeling of plasma HDL. Several neuroprotective properties have been ascribed to HDL. We reported earlier that liver X receptor (LXR) activation promotes cellular cholesterol efflux and formation of HDL-like particles in an established in vitro model of the blood-brain barrier (BBB) consisting of primary porcine brain capillary endothelial cells (pBCEC). Here, we report PLTP synthesis, regulation, and its key role in HDL metabolism at the BBB. We demonstrate that PLTP is highly expressed and secreted by pBCEC. In a polarized in vitro model mimicking the BBB, pBCEC secreted phospholipid-transfer active PLTP preferentially to the basolateral ("brain parenchymal") compartment. PLTP expression levels and phospholipid transfer activity were enhanced (up to 2.5-fold) by LXR activation using 24(S)-hydroxycholesterol (a cerebral cholesterol metabolite) or TO901317 (a synthetic LXR agonist). TO901317 administration elevated PLTP activity in BCEC from C57/BL6 mice. Preincubation of HDL3 with human plasma-derived active PLTP resulted in the formation of smaller and larger HDL particles and enhanced the capacity of the generated HDL particles to remove cholesterol from pBCEC by up to 3-fold. Pre-β-HDL, detected by two-dimensional crossed immunoelectrophoresis, was generated from HDL3 in pBCEC-derived supernatants, and their generation was markedly enhanced (1.9-fold) upon LXR activation. Furthermore, RNA interference-mediated PLTP silencing (up to 75%) reduced both apoA-I-dependent (67%) and HDL3-dependent (30%) cholesterol efflux from pBCEC. Based on these findings, we propose that PLTP is actively involved in lipid transfer, cholesterol efflux, HDL genesis, and remodeling at the BBB.
authors.affiliation: From the Institute of Pathophysiology and Immunology.
authors.forename: Anil Paul
authors.initials: AP
authors.lastname: Chirackal Manavalan
authors.forename: Alexandra
authors.initials: A
authors.lastname: Kober
authors.forename: Jari
authors.initials: J
authors.lastname: Metso
authors.forename: Ingrid
authors.initials: I
authors.lastname: Lang
authors.forename: Tatjana
authors.initials: T
authors.lastname: Becker
authors.forename: Karin
authors.initials: K
authors.lastname: Hasslitzer
authors.forename: Martina
authors.initials: M
authors.lastname: Zandl
authors.forename: Elham
authors.initials: E
authors.lastname: Fanaee-Danesh
authors.forename: Jyotsna Brijesh
authors.initials: JB
authors.lastname: Pippal
authors.forename: Vinay
authors.initials: V
authors.lastname: Sachdev
authors.forename: Dagmar
authors.initials: D
authors.lastname: Kratky
authors.forename: Jasminka
authors.initials: J
authors.lastname: Stefulj
authors.forename: Matti
authors.initials: M
authors.lastname: Jauhiainen
authors.forename: Ute
authors.initials: U
authors.lastname: Panzenboeck
mesh_terms: D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000378:metabolism; D000818:Animals; D016632:Apolipoprotein A-I / Q000378:metabolism; D001692:Biological Transport; D001812:Blood-Brain Barrier / Q000166:cytology* / Q000378:metabolism*; D002196:Capillaries / Q000166:cytology; D016764:Cell Polarity; D002784:Cholesterol / Q000378:metabolism; D042783:Endothelial Cells / Q000378:metabolism*; D020868:Gene Silencing; D006801:Humans; D008075:Lipoproteins, HDL / Q000096:biosynthesis*; D000071518:Liver X Receptors; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D057093:Orphan Nuclear Receptors / Q000819:agonists / Q000378:metabolism; D049294:Phospholipid Transfer Proteins / Q000378:metabolism*; D020836:Protein Structure, Quaternary; D034421:Sus scrofa; D015854:Up-Regulation
chemical_list: D016229:Amyloid beta-Peptides; D016632:Apolipoprotein A-I; D008075:Lipoproteins, HDL; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D049294:Phospholipid Transfer Proteins; D002784:Cholesterol
keywords: Aβ; Blood-Brain Barrier; Brain; Cholesterol; Cholesterol Efflux; Endothelium; HDL; LXRs; Nuclear Receptors; Pre-β HDL