Expression of ABCG1, but Not ABCA1, Correlates with Cholesterol Release by Cerebellar Astroglia

Abstract

Central nervous system lipoproteins mediate the exchange of cholesterol between cells and support synaptogenesis and neuronal growth. The primary source of lipoproteins in the brain is astroglia cells that synthesize and secrete apolipoprotein (apo) E in high density lipoprotein-like particles. Small quantities of apoA1, derived from the peripheral circulation, are also present in the brain. In addition to the direct secretion of apoE-containing lipoproteins from astroglia, glia-derived lipoproteins are thought to be formed by cholesterol efflux to extracellular apolipoproteins via ATP-binding cassette (ABC) transporters. We used cultured cerebellar murine astroglia to investigate the relationship among cholesterol availability, apoE secretion, expression of ABCA1 and ABCG1, and cholesterol efflux. In many cell types, cholesterol content, ABCA1 expression, and cholesterol efflux are closely correlated. In contrast, cholesterol enrichment of glia failed to increase ABCA1 expression, although ABCG1 expression and cholesterol efflux to apoA1 were increased. Moreover, the liver X receptor (LXR) agonist TO901317 up-regulated ABCA1 and ABCG1 expression in glia without stimulating cholesterol efflux. Larger lipoproteins were generated when glia were enriched with cholesterol, whereas treatment with the LXR agonist produced smaller particles that were eliminated when the glia were loaded with cholesterol. We also used glia from ApoE ؊/؊ mice to distinguish between direct lipoprotein secretion and the extracellular generation of lipoproteins. Our observations indicate that partially lipidated apoE, secreted directly by glia, is likely to be the major extracellular acceptor of cholesterol released from glia in a process mediated by ABCG1.The human brain contains 15-20% of total body cholesterol but represents only ϳ5% of total body weight (1). Cholesterol is a key component of all membranes, including myelin, in the central nervous system (CNS), 4 and cholesterol is synthesized continuously, albeit at a low rate, in the adult brain (1). All cholesterol in the CNS is synthesized within the CNS rather than being imported from the periphery (2). As a mechanism for maintaining cholesterol homeostasis in the CNS, cholesterol can be converted into the more polar 24-hydroxycholesterol, which is released into the circulation by a subset of neurons (3, 4). Because cholesterol metabolism and distribution are not uniform across all cell types of the brain, an efficient system is necessary for the transport of cholesterol, and probably other lipids, among cells of the CNS. In the CNS, as in the periphery, cholesterol exchange between cells is mediated by lipoproteins. Lipoproteins in the CNS are derived from glia (astrocytes and microglia), which synthesize and secrete apolipoprotein (apo) E and apoJ (5-7) as well as apoD (8). Unlike the plasma, in which apoA1 is the most abundant apolipoprotein, apoE is the major apolipoprotein in the CNS (9, 10). Glia-derived lipoproteins play important roles in the brain by enhancing synaptogenesi...

ABC transporters, neural stem cells and neurogenesis – a different perspective

“…With its expression in liver and brain, ABCB1 -the prototype of the B subclass of transporters -and ABCA1 regulate the high-density lipoprotein levels in the plasma and cholesterol contents of several cell types in these organs [106][107][108][109][110][111][112][113][114]. Most interestingly, the ABCB1 transporter also shows strong expression in neurons of the hippocampus formation, particularly in the granule cells of the DG [85].…”

Selection of reference genes for gene expression studies in rat oligodendrocytes using quantitative real time PCR

“…GAPDH, 18S or CycA (Abildayeva et al, 2006;Karten et al, 2006;Liang et al, 2004). Recently, suitable reference genes were described for rat brain tissue and hippocampal neurons under different experimental conditions (Bonefeld et al, 2008;Langnaese et al, 2008;Santos and Duarte, 2008).…”

Differential regulation of ABCA1 and ABCG1 gene expressions in the remodeling mouse hippocampus after entorhinal cortex lesion and liver-X receptor agonist treatment

“…While some studies failed to detect any effect of ABCG1 overexpression or deficiency on cholesterol efflux and brain lipid levels in apoE deficient (Burgess et al, 2008a) and PDAPP transgenic mice (Burgess et al, 2008b), others report positive correlations between ABCG1 expression and peripheral lipid tissue levels (Kennedy et al, 2005). ABCA1 has repeatedly been reported to act in concert with ABCG1, and both were shown to act sequentially in promoting phospholipids and cholesterol efflux from peripheral cell and to facilitate apoE-HDL lipidation (Gelissen et al, 2006;Karten et al, 2006;Kennedy et al, 2005;Vaughan and Oram, 2006). Cholesterol loading in vitro enhances ABCG1, but not ABCA1, expression and correlates best with cholesterol efflux from astrocytes (Karten et al, 2006).…”

“…ABCG1 has been associated with intracellular cholesterol trafficking and efflux (Abildayeva et al, 2006;Burgess et al, 2008aBurgess et al, , 2008bKarten et al, 2006;Klucken et al, 2000;Vaughan and Oram, 2005), whereas ABCA1 has been linked to secretion and lipidation of apoA1 with cholesterol and HDL production in the plasma, CSF and brain (Hirsch-Reinshagen et al, 2004;Koldamova et al, 2003;Wahrle et al, 2004). Furthermore, in vitro work demonstrated that the coordinated action of ABCA1 and G1 is required for optimal removal of cellular cholesterol (Gelissen et al, 2006;Vaughan and Oram, 2006).…”