Function of ATP-binding cassette transporter A1 (ABCA1) in apoA-Icontaining HDL generation of astroglia.

Abstract

Apolipoprotein A-I (apoA-I) is one of the most abundant apolipoproteins along with apoE in the cerebrospinal fluid (CSF). It is thought that apoA-I produced by brain capillary endothelial cells in the brain, while apoE is mainly done by astrocytes. Astrocytes generate not only apoE-containing highdensity lipoprotein-like particle (apoE/HDL) using endogenous apoE but also apoA-I/HDL through the interaction with exogenous apoA-I. Astrocytes generate both apoA-I/HDL and apoE/HDL dependently on a transmembrane protein, ATP-binding cassette transporter A1 (ABCA1).ABCA1 is widely localized in both caveolin-1-rich fraction containing lipid raft domains and non-caveolin-1fraction of the plasma membrane in rat astrocytes unlike peripheral cells. Exogenous apoA-I binds to ABCA1 localized in the non-caveolin-1-fraction with slightly higher densities than the caveolin-1-rich fraction of plasma membrane but not in the complete non-caveolin-1-fraction with highest density, while the endogenous apoE is associated with ABCA1 in the caveolin-1-rich fraction of rat astrocytes. After the association with ABCA1, exogenous apoA-I stimulates the phosphorylation of ABCA1associated phospholipase C? (PL-C?) in the intracellular site and promotes the translocation of phosphorylated PL-C? to the cytosolic lipid-protein particles (CLPPs) in the cytosol fraction of rat astrocytes. The CLPPs are intracellular HDL-like lipid-protein complexes with densities of 1.09-1.16 g/ml and diameters of 17-18 nm, and composed of lipids such as cholesterol, sphingomyelin, and phosphatidylcholine with proteins such as caveolin-1, protein kinase C? (PK-C?), and cyclophilin A in astrocytes. Furthermore, the newly synthesized cholesterol is translocated along with sphingomyelin and phosphatidylcholine from the endoplasmic reticulum/Golgi apparatus (ER/Golgi) to the CLPPs in the cytosol and is transported to the plasma membrane through the interaction with microtubules. Thus, the newly synthesized cholesterol is transferred to exogenous apoA-I in the extracellular space dependently on the association of apoA-I with ABCA1 and the series of intracellular reactions in the CLPPs.