Journal article
ABCG1 influences the brain cholesterol biosynthetic pathway but does not affect amyloid precursor protein or apolipoprotein E metabolism in vivo
Journal of Lipid Research, Vol.49(6), pp.1254-1267
2008
Abstract
Cholesterol homeostasis is of emerging therapeutic importance for Alzheimer's disease (AD). Agonists of liver-X-receptors (LXRs) stimulate several genes that regulate cholesterol homeostasis, and synthetic LXR agonists decrease neuropathological and cognitive phenotypes in AD mouse models. The cholesterol transporter ABCG1 is LXR-responsive and highly expressed in brain. In vitro, conflicting reports exist as to whether ABCG1 promotes or impedes Aβ production. To clarify the in vivo roles of ABCG1 in Aβ metabolism and brain cholesterol homeostasis, we assessed neuropathological and cognitive outcome measures in PDAPP mice expressing excess transgenic ABCG1. A 6-fold increase in ABCG1 levels did not alter Aβ, amyloid, apolipoprotein E levels, cholesterol efflux, or cognitive performance in PDAPP mice. Furthermore, endogenous murine Aβ levels were unchanged in both ABCG1-overexpressing or ABCG1-deficient mice. These data argue against a direct role for ABCG1 in AD. However, excess ABCG1 is associated with decreased levels of sterol precursors and increased levels of SREBP-2 and HMG-CoA-reductase mRNA, whereas deficiency of ABCG1 leads to the opposite effects. Although functions for ABCG1 in cholesterol efflux and Aβ metabolism have been proposed based on results with cellular model systems, the in vivo role of this enigmatic transporter may be largely one of regulating the sterol biosynthetic pathway. Copyright © 2008 by the American Society for Biochemistry and Molecular Biology, Inc.
Details
- Title
- ABCG1 influences the brain cholesterol biosynthetic pathway but does not affect amyloid precursor protein or apolipoprotein E metabolism in vivo
- Authors
- B L Burgess (Author) - University of British Columbia, CanadaP F Parkinson (Author) - University of British Columbia, CanadaM M Racke (Author) - Lilly Research Laboratories, United StatesV Hirsch-Reinshagen (Author) - University of British Columbia, CanadaJ Fan (Author) - University of British Columbia, CanadaC Wong (Author) - University of British Columbia, CanadaS Stukas (Author) - University of British Columbia, CanadaL Theroux (Author) - McGill Centre for Studies on Aging, CanadaJ Y Chan (Author) - University of British Columbia, CanadaJames J Donkin (Author) - University of British Columbia, CanadaA Wilkinson (Author) - University of British Columbia, CanadaD Balik (Author) - University of British Columbia, CanadaB Christie (Author) - University of Victoria, CanadaJ Poirier (Author) - McGill Centre for Studies on Aging, CanadaD Lütjohann (Author) - University of Bonn, GermanyR B DeMattos (Author) - University of British Columbia, CanadaC L Wellington (Author) - University of British Columbia, Canada
- Publication details
- Journal of Lipid Research, Vol.49(6), pp.1254-1267
- Publisher
- American Society for Biochemistry and Molecular Biology, Inc.
- Date published
- 2008
- DOI
- 10.1194/jlr.M700481-JLR200
- ISSN
- 0022-2275
- Copyright note
- Copyright © 2008 by the American Society for Biochemistry and Molecular Biology, Inc. The published version is reproduced here in accordance with the publisher's copyright policy.
- Organisation Unit
- UniSC Clinical Trials Centre; University of the Sunshine Coast, Queensland
- Language
- English
- Record Identifier
- 99450684402621
- Output Type
- Journal article
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