The LXR agonist GW3965 increases apoA-I protein levels in the central nervous system independent of ABCA1

S Stukas; S May; A Wilkinson; J Chan; James J Donkin; C L Wellington

doi:10.1016/j.bbalip.2011.08.014

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The LXR agonist GW3965 increases apoA-I protein levels in the central nervous system independent of ABCA1

Journal article

Peer reviewed

The LXR agonist GW3965 increases apoA-I protein levels in the central nervous system independent of ABCA1

S Stukas, S May, A Wilkinson, J Chan, James J Donkin and C L Wellington

Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids, Vol.1821(3), pp.536-546

2012

DOI: https://doi.org/10.1016/j.bbalip.2011.08.014

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Abstract

Apo-A-I

apoE

ABCA1

LXR

brain lipid metabolism

Lipoprotein metabolism in the central nervous system (CNS) is based on high-density lipoprotein-like particles that use apoE as their predominant apolipoprotein rather than apoA-I. Although apoA-I is not expressed in astrocytes and microglia, which produce CNS apoE, apoA-I is reported to be expressed in porcine brain capillary endothelial cells and also crosses the blood-brain barrier (BBB). These mechanisms allow apoA-I to reach concentrations in cerebrospinal fluid (CSF) that are approximately 0.5% of its plasma levels. Recently, apoA-I has been shown to enhance cognitive function and reduce cerebrovascular amyloid deposition in Alzheimer's Disease (AD) mice, raising questions about the regulation and function of apoA-I in the CNS. Peripheral apoA-I metabolism is highly influenced by ABCA1, but less is known about how ABCA1 regulates CNS apoA-I. We report that ABCA1 deficiency leads to greater retention of apoA-I in the CNS than in the periphery. Additionally, treatment of symptomatic AD mice with GW3965, an LXR agonist that stimulates ABCA1 expression, increases apoA-I more dramatically in the CNS compared to the periphery. Furthermore, GW3965-mediated up-regulation of CNS apoA-I is independent of ABCA1. Our results suggest that apoA-I may be regulated by distinct mechanisms on either side of the BBB and that apoA-I may serve to integrate peripheral and CNS lipid metabolism. This article is part of a Special Issue entitled Advances in High Density Lipoprotein Formation and Metabolism: A Tribute to John F. Oram (1945-2010). © 2011 Elsevier B.V. All rights reserved.

Details

Title: The LXR agonist GW3965 increases apoA-I protein levels in the central nervous system independent of ABCA1
Authors: S Stukas (Author) - University of British Columbia, Canada
S May (Author) - University of British Columbia, Canada
A Wilkinson (Author) - University of British Columbia, Canada
J Chan (Author) - University of British Columbia, Canada
James J Donkin (Author) - University of British Columbia, Canada
C L Wellington (Author) - University of British Columbia, Canada
Publication details: Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids, Vol.1821(3), pp.536-546
Publisher: Elsevier BV
Date published: 2012
DOI: 10.1016/j.bbalip.2011.08.014
ISSN: 1388-1981
Organisation Unit: UniSC Clinical Trials Centre; University of the Sunshine Coast, Queensland
Language: English
Record Identifier: 99451081802621
Output Type: Journal article

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Collaboration types: Domestic collaboration
Web Of Science research areas: Biochemistry & Molecular Biology; Biophysics; Cell Biology

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