Abstract
The central nervous system (CNS) is composed of numerous neural cells such as neurons and glias that have wide cell surface and numerous processes covered with plasma membranes. As the plasma membrane is enriched in cholesterol, the CNS composed of numerous neural cells with wide plasma membrane is a cholesterol- rich organ. Because inhibition of cholesterol supply induces cell death into neurons, the CNS is also an organ to highly require cholesterol. It is known that intercellular cholesterol transport is mainly maintained by generation of apolipoprotein- mediated high-density lipoproteins (HDL) in astrocytes and its supply to neuronal cells. Therefore, a study to elucidate a mechanism underlying the generation of HDL in astrocytes is one of important research subjects to understand cholesterol homeostasis in the brain.
In this context, it is of note that we have found cytosolic lipid-protein particles (CLPPs) to mediate intracellular cholesterol transport leading to HDL generation in rat astrocytes. The CLPPs are lipoprotein- like complexes composed of proteins such as caveolin-1 and cyclophilin A and lipids such as cholesterol, sphingomyelin, and phosphatidylcholine in the cytosol. It was shown by using specific enzyme inhibitors that exogenous apolipoprotein A-I (apoA-I) interacts with the membraneassociated ATP-binding cassette transporter A1 (ABCA1) to promote the CLPP-mediated intracellular transport of newly synthesized cholesterol through activation of ABCA1-binding phospholipase Cγ and protein kinase Cα. An inhibitor of phosphatidylcholine-specific phospholipase C, D609, reduces sphingomyelin synthesis and apoA-I-mediated HDL generation. These findings suggest that sphingomyelin synthesis is important for intracellular cholesterol transport to the plasma membrane and cholesterol efflux to generate apoA-I-containing HDL (apoA-I/HDL). A cyclophilin A inhibitor, cyclosporin A (Cs-A), suppresses not only exogenous apoA-I-mediated cholesterol efflux but also intracellular cholesterol transport through the inhibition of assembly of caveolin-1 and cholesterol to the CLPPs. Based on these findings, it is suggested that the CLPPs contribute to the intracellular cholesterol transport and cholesterol efflux to generate apoA-I/HDL. The mechanism underlying intracellular cholesterol transport, by which HDL generation and cholesterol homeostasis are regulated in the brain, is discussed focusing on our findings in this review.
Keywords: Astrocytes, apoA-I, HDL, sphingomyelinase, sphingomyelin synthesis, D609.
Graphical Abstract
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