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A more recent version of this article appeared on January 1, 2008

Papers In Press, published online ahead of print October 4, 2007
J. Lipid Res., doi:10.1194/jlr.M700364-JLR200
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Submitted on August 14, 2007
Revised on September 28, 2007
Accepted on October 3, 2007

ABCG1 and ABCG4 are co-expressed in neurons and astrocytes of the CNS and regulate cholesterol homeostasis through SREBP-2

Paul T. Tarr and Peter A. Edwards

Biological Chemistry, University of California Los Angeles, Los Angeles, CA 90095

Corresponding Author: pedwards{at}mednet.ucla.edu

Herein we describe the initial characterization of Abcg4-/- mice and identify overlapping functions of ABCG4 and ABCG1 in the brain. Histological examination of tissues from Abcg4+/-/nlsLacZ and Abcg1+/-/nlsLacZ mice demonstrates that co-expression of Abcg4 and Abcg1 is restricted to neurons and astrocytes of the CNS. Interestingly, Abcg4 mRNA is undetectable outside the CNS, thus contrasting with the broad tissue and cellular expression of Abcg1. We also utilized primary astrocytes, microglia, neurons, and macrophages to demonstrate that the expression of Abcg1, but not Abcg4, is induced following activation of LXR. Cellular localization studies demonstrated that both proteins reside in RhoB positive endocytic vesicle membranes. Furthermore, over-expression of either ABCG1 or ABCG4 increased the processing of SREBP-2 to the transcriptionally active protein, thus accounting for the observed increase in expression of SREBP-2 target genes and cholesterol synthesis. Consistent with these latter results, we show that the expression levels of the same SREBP-2 target genes are repressed in the brains of Abcg1-/- and, to a lesser extent, Abcg4-/- mice. Based on the results of the current study we propose that ABCG1 and ABCG4 mediate intracellular vesicular transport of cholesterol/sterols within both neurons and astrocytes to regulate cholesterol transport in the brain.


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