Phospholipid transfer protein is expressed in cerebrovascular endothelial cells and involved in HDL biogenesis and remodeling at the blood- brain barrier [Cell Biology]

December 25th, 2013 by Chirackal Manavalan, A. P., Kober, A., Metso, J., Lang, I., Becker, T., Hasslitzer, K., Zandl, M., Fanaee-Danesh, E., Pippal, J. B., Sachdev, V., Kratky, D., Stefulj, J., Jauhiainen, M., Panzenboeck, U.

Phospholipid transfer protein (PLTP) is a key protein involved in biogenesis and remodeling of plasma HDL. Several neuro-protective 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. Pre-incubation 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. Preβ-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.
  • Posted in Journal of Biological Chemistry, Publications
  • Comments Off on Phospholipid transfer protein is expressed in cerebrovascular endothelial cells and involved in HDL biogenesis and remodeling at the blood- brain barrier [Cell Biology]