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Papers In Press, published online ahead of print January 1, 2010
J. Lipid Res., doi:10.1194/M900250-JLR200

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Journal of Lipid Research, Vol. 51, 169-181, January 2010
Copyright © 2010 by American Society for Biochemistry and Molecular Biology

Differential expression and function of ABCG1 and ABCG4 during development and aging^[S]

Dragana D. Bojanic^*, Paul T. Tarr, Greg D. Gale, Desmond J. Smith, Dean Bok^**,,, Bryan Chen^**, Steven Nusinowitz^*, Anita Lövgren-Sandblom^***, Ingemar Björkhem^*** and Peter A. Edwards^1,*,,

^* Department of Biological Chemistry at UCLA Los Angeles, CA 90095
Department of Medicine at UCLA Los Angeles, CA 90095
David Geffen School of Medicine and Molecular Biology Institute at UCLA Los Angeles, CA 90095
Department of Molecular and Medical Pharmacology, Los Angeles, CA 90095
^** Department of Jules Stein Eye Institute, Los Angeles, CA 90095
Department of Neurobiology Los Angeles, CA 90095
Department of Brain Research Institute, Los Angeles, CA 90095
^*** Karolinska Institutet, Sweden
Division of Biology California Institute of Technology, Pasadena, CA 91125

¹ To whom correspondence should be addressed. e-mail: pedwards{at}mednet.ucla.edu

ABCG1 and ABCG4 are highly homologous members of the ATP binding cassette (ABC) transporter family that regulate cellular cholesterol homeostasis. In adult mice, ABCG1 is known to be expressed in numerous cell types and tissues, whereas ABCG4 expression is limited to the central nervous system (CNS). Here, we show significant differences in expression of these two transporters during development. Examination of β-galactosidase-stained tissue sections from Abcg1^–/–LacZ and Abcg4^–/–LacZ knockin mice shows that ABCG4 is highly but transiently expressed both in hematopoietic cells and in enterocytes during development. In contrast, ABCG1 is expressed in macrophages and in endothelial cells of both embryonic and adult liver. We also show that ABCG1 and ABCG4 are both expressed as early as E12.5 in the embryonic eye and developing CNS. Loss of both ABCG1 and ABCG4 results in accumulation in the retina and/or brain of oxysterols, in altered expression of liver X receptor and sterol-regulatory element binding protein-2 target genes, and in a stress response gene. Finally, behavioral tests show that Abcg4^–/– mice have a general deficit in associative fear memory. Together, these data indicate that loss of ABCG1 and/or ABCG4 from the CNS results in changes in metabolic pathways and in behavior.

Supplementary key words oxysterols • liver X receptor • sterol regulatory element binding protein-2 • central nervous system

Abbreviations: ABC, ATP binding cassette; CNS, central nervous system; DKO, double knockout; ERG, electroretinography; LTP, long-term potentiation; LXR, liver X receptor; TBST, TBS-1% Tween 20

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