Abstract
ABCA1 is a cholesterol transporter that is widely expressed throughout the body. Outside the central nervous system (CNS), ABCA1 functions in the biogenesis of high-density lipoprotein (HDL), where it mediates the efflux of cholesterol and phospholipids to apolipoprotein (apo) A-I. Deficiency of ABCA1 results in lack of circulating HDL and greatly reduced levels of apoA-I. ABCA1 is also expressed in cells within the CNS, but its roles in brain lipid metabolism are not yet fully understood. In the brain, glia synthesize the apolipoproteins involved in CNS lipid metabolism. Here we demonstrate that glial ABCA1 is required for cholesterol efflux to apoA-I and plays a key role in facilitating cholesterol efflux to apoE, which is the major apolipoprotein in the brain. In both astrocytes and microglia, ABCA1 deficiency reduces lipid efflux to exogenous apoE. The impaired ability to efflux lipids in ABCA1-/- glia results in lipid accumulation in both astrocytes and microglia under normal culture conditions. Additionally, apoE secretion is compromised in ABCA1-/- astrocytes and microglia. In vivo, deficiency of ABCA1 results in a 65% decrease in apoE levels in whole brain, and a 75-80% decrease in apoE levels in hippocampus and striatum. Additionally, the effect of ABCA1 on apoE is selective, as apoJ levels are unchanged in brains of ABCA1-/- mice. Taken together, these results show that glial ABCA1 is a key influence on apoE metabolism in the CNS.
Highlights
ABCA1 is a member of the ATP-binding cassette superfamily of transporters that transport substrates across membranes [1,2,3]
The identification of ABCA1 as an essential protein for the production of high density lipoproteins (HDL) has generated great interest in understanding ABCA1 function, in tissues such as the liver and macrophages that are relevant to HDL metabolism and atherosclerosis
Lipid metabolism in the central nervous system (CNS) is largely independent of that outside the CNS, there are several points of intersection that may be highly relevant to neurodegenerative diseases, Alzheimer’s disease (AD)
Summary
Mice—ABCA1-deficient mice were generously provided by Dr Omar Francone of Pfizer Global Research and Development (Groton). Wildtype DBA1/J, C57Bl/6, apoE-deficient and apoA-I-deficient mice were obtained from Jackson Laboratories. Animals were maintained on regular chow (PMI Lab Diet) for all experiments. All procedures involving experimental animals were performed in accordance with protocols
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