ABCG1 and ABCG4 are coexpressed in neurons and astrocytes of the CNS and regulate cholesterol homeostasis through SREBP-2.
Here, 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 coexpression of Abcg4 and Abcg1 is restricted to neurons and astrocytes of the central nervous system (CNS). Interestingly, Abcg4 mRNA is undetectable outside the CNS, in contrast with the broad tissue and cellular expression of Abcg1. We also used primary astrocytes, microglia, neurons, and macrophages to demonstrate that the expression of Abcg1, but not Abcg4, is induced after the activation of liver X receptor. Cellular localization studies demonstrated that both proteins reside in RhoB-positive endocytic vesicle membranes. Furthermore, overexpression of either ABCG1 or ABCG4 increased the processing of sterol-regulatory element binding protein 2 (SREBP-2) to the transcriptionally active protein, thus accounting for the observed increase in the 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 the intracellular vesicular transport of cholesterol/sterols within both neurons and astrocytes to regulate cholesterol transport in the brain.
Tarr
Paul T
PT
Department of Biological Chemistry, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA 90095, USA.
Edwards
Peter A
PA
D000070996:ATP Binding Cassette Transporter, Subfamily G; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism*; D000818:Animals; D001253:Astrocytes / Q000166:cytology / Q000378:metabolism*; D001921:Brain / Q000166:cytology / Q000378:metabolism*; D002784:Cholesterol / Q000096:biosynthesis / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism; D011992:Endosomes / Q000378:metabolism; D050356:Lipid Metabolism; D008074:Lipoproteins / Q000378:metabolism*; D000071518:Liver X Receptors; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D057093:Orphan Nuclear Receptors; D012333:RNA, Messenger / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D051782:Sterol Regulatory Element Binding Protein 2 / Q000378:metabolism*
C487540:ABCG1 protein, mouse; D000070996:ATP Binding Cassette Transporter, Subfamily G; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018528:ATP-Binding Cassette Transporters; C486685:Abcg4 protein, mouse; D004268:DNA-Binding Proteins; D008074:Lipoproteins; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D051782:Sterol Regulatory Element Binding Protein 2; D002784:Cholesterol