Expression and Regulation of Multiple Murine ATP-binding Cassette Transporter G1 mRNAs/Isoforms That Stimulate Cellular Cholesterol Efflux to High Density Lipoprotein

Abstract

The murine Abcg1 gene is reported to consist of 15 exons that encode a single mRNA (herein referred to as Abcg1-a) and protein. We now demonstrate that (i) the murine gene contains two additional coding exons downstream of exon 1, (ii) transcription involves the use of multiple promoters, and (iii) the RNA undergoes alternative splicing reactions. As a result, three mRNAs are expressed that encode three putative protein isoforms that differ at their amino terminus. ABCG1 transcripts are induced in vivo in multiple tissues in response to the liver X receptor ligand T0901317. Identification and characterization of four liver X receptor response elements in the intron downstream of exon 2 provides a mechanism by which this induction occurs. Importantly, cholesterol efflux to high density lipoprotein was stimulated following transfection of Hek293 cells with plasmids encoding individual ABCG1 isoforms. In situ hybridization studies in embryonic day 11.5–15.5 mouse embryos revealed strong expression of ABCG1 transcripts in the olfactory epithelium, hind brain, eye, and dorsal root ganglia. The relatively high levels of expression in neuronal tissues and the eye suggest that ABCG1-dependent cholesterol efflux may be critical for normal neuronal function in addition to its role in macrophages. The murine Abcg1 gene is reported to consist of 15 exons that encode a single mRNA (herein referred to as Abcg1-a) and protein. We now demonstrate that (i) the murine gene contains two additional coding exons downstream of exon 1, (ii) transcription involves the use of multiple promoters, and (iii) the RNA undergoes alternative splicing reactions. As a result, three mRNAs are expressed that encode three putative protein isoforms that differ at their amino terminus. ABCG1 transcripts are induced in vivo in multiple tissues in response to the liver X receptor ligand T0901317. Identification and characterization of four liver X receptor response elements in the intron downstream of exon 2 provides a mechanism by which this induction occurs. Importantly, cholesterol efflux to high density lipoprotein was stimulated following transfection of Hek293 cells with plasmids encoding individual ABCG1 isoforms. In situ hybridization studies in embryonic day 11.5–15.5 mouse embryos revealed strong expression of ABCG1 transcripts in the olfactory epithelium, hind brain, eye, and dorsal root ganglia. The relatively high levels of expression in neuronal tissues and the eye suggest that ABCG1-dependent cholesterol efflux may be critical for normal neuronal function in addition to its role in macrophages. There are more than 373 members in the ATP-binding cassette (ABC) 1The abbreviations used are: ABC, ATP-binding cassette; LXR, liver X receptor; LXRE, LXR response element; RXR, retinoid X receptor; HDL, high density lipoprotein; UTR, untranslated region; EMSA, electrophoretic mobility shift assay; TK, thymidine kinase; RACE, rapid amplification of cDNA ends. superfamily of transmembrane transporters that are expressed in species as diverse as plants, yeast, Drosophila, and mammals (1Sanchez-Fernandez R. Davies T.G. Coleman J.O. Rea P.A. J. Biol. Chem. 2001; 276: 30231-30244Abstract Full Text Full Text PDF PubMed Scopus (411) Google Scholar). To date, 52 members of this superfamily have been identified in mammals (2Dean M. Hamon Y. Chimini G. J. Lipid Res. 2001; 42: 1007-1017Abstract Full Text Full Text PDF PubMed Google Scholar, 3Dean M. Rzhetsky A. Allikmets R. Genome Res. 2001; 11: 1156-1166Crossref PubMed Scopus (1499) Google Scholar). ABC transporters have been subdivided into full and half transporters; full transporters contain two ATP-binding domains and two multitransmembrane domains, each typically containing six transmembrane α-helices. In contrast, half transporters contain one ATP-binding cassette and one transmembrane domain and must dimerize to form a functional pump (4Ambudkar S.V. Gottesman M.M. Abelson J.N. Simon M.I. ABC Transporters: Biochemical, Cellular, and Molecular Aspects. 292. Academic Press, San Diego, CA1998: 101-115Google Scholar, 5Higgins C.F. Annu. Rev. Cell Biol. 1992; 8: 67-113Crossref PubMed Scopus (3375) Google Scholar, 6Luciani M.F. Chimini G. EMBO J. 1996; 15: 226-235Crossref PubMed Scopus (250) Google Scholar). Binding and hydrolysis of ATP by these membrane-bound pumps provides the energy to transport small hydrophobic substrates from the cytoplasm either to the outside of the cell or into intracellular compartments such as the endoplasmic reticulum, peroxisomes, or mitochondria (5Higgins C.F. Annu. Rev. Cell Biol. 1992; 8: 67-113Crossref PubMed Scopus (3375) Google Scholar, 7Childs S. Ling V. Important Adv. Oncol. 1994; : 21-36PubMed Google Scholar). The importance of these proteins is illustrated by the fact that numerous human diseases are caused by mutations in specific members of the ABC transporter superfamily (2Dean M. Hamon Y. Chimini G. J. Lipid Res. 2001; 42: 1007-1017Abstract Full Text Full Text PDF PubMed Google Scholar, 3Dean M. Rzhetsky A. Allikmets R. Genome Res. 2001; 11: 1156-1166Crossref PubMed Scopus (1499) Google Scholar, 8Klein I. Sarkadi B. Varadi A. Biochim. Biophys. Acta. 1999; 1461: 237-262Crossref PubMed Scopus (511) Google Scholar, 9Allikmets R. Gerrard B. Hutchinson A. Dean M. Hum. Mol. Genet. 1996; 5: 1649-1655Crossref PubMed Scopus (283) Google Scholar). ABC transporters are further subdivided into seven groups, ABCA through ABCG. Members of the ABCG subtype (ABCG1, ABCG2, ABCG3, ABCG4, ABCG5, ABCG8, and Drosophila white, brown, and scarlet) are unique in that the ATP-binding cassette of these half transporters is at the amino terminus and the transmembrane domains are at the carboxyl terminus of the protein. In the original studies the cDNAs corresponding to ABCG1 were referred to as either ABC8 and/or white (10Savary S. Denizot F. Luciani M. Mattei M. Chimini G. Mamm. Genome. 1996; 7: 673-676Crossref PubMed Scopus (52) Google Scholar, 11Croop J.M. Tiller G.E. Fletcher J.A. Lux M.L. Raab E. Goldenson D. Son D. Arciniegas S. Wu R.L. Gene (Amst.). 1997; 185: 77-85Crossref PubMed Scopus (78) Google Scholar). Both the murine and human cDNAs encode proteins of ∼67 kDa that have 34% amino acid identity with the Drosophila white protein (10Savary S. Denizot F. Luciani M. Mattei M. Chimini G. Mamm. Genome. 1996; 7: 673-676Crossref PubMed Scopus (52) Google Scholar, 11Croop J.M. Tiller G.E. Fletcher J.A. Lux M.L. Raab E. Goldenson D. Son D. Arciniegas S. Wu R.L. Gene (Amst.). 1997; 185: 77-85Crossref PubMed Scopus (78) Google Scholar). Drosophila white dimerizes with either scarlet or brown to form heterodimers (white/scarlet or white/brown, respectively) that transport precursors of the ommochromes and pteridines into the pigment granule of the fly eye (12Mackenzie S.M. Howells A.J. Cox G.B. Ewart G.D. Genetica (Dordrecht). 2000; 108: 239-252Crossref PubMed Scopus (92) Google Scholar, 13Dreesen T.D. Johnson D.H. Henikoff S. Mol. Cell. Biol. 1988; 8: 5206-5215Crossref PubMed Scopus (174) Google Scholar, 14Tearle R.G. Belote J.M. McKeown M. Baker B.S. Howells A.J. Genetics. 1989; 122: 595-606Crossref PubMed Google Scholar, 15Pepling M. Mount S.M. Nucleic Acids Res. 1990; 18: 1633Crossref PubMed Scopus (44) Google Scholar). However, no mammalian homologues of Drosophila brown or scarlet that might function as the heterodimeric partner of ABCG1 have been identified. The mammalian ABCG4 protein has 94% amino acid identity with ABCG1, consistent with gene duplication (16Annilo T. Tammur J. Hutchinson A. Rzhetsky A. Dean M. Allikmets R. Cytogenet. Cell Genet. 2001; 94: 196-201Crossref PubMed Scopus (44) Google Scholar, 17Oldfield S. Lowry C. Ruddick J. Lightman S. Biochim. Biophys. Acta. 2002; 1591: 175-179Crossref PubMed Scopus (51) Google Scholar). However, ABCG4 expression is reported to be limited to the brain and eye (17Oldfield S. Lowry C. Ruddick J. Lightman S. Biochim. Biophys. Acta. 2002; 1591: 175-179Crossref PubMed Scopus (51) Google Scholar) and this would preclude the formation of obligate ABCG1/ABCG4 functional heterodimers in many tissues. In an attempt to determine the function for mammalian ABCG1, Klucken et al. (18Klucken J. Buchler C. Orso E. Kaminski W.E. Porsch-Ozcurumez M. Liebisch G. Kapinsky M. Diederich W. Drobnik W. Dean M. Allikmets R. Schmitz G. Proc. Natl. S. A. 2000; PubMed Scopus Google Scholar) human with to in expression of a protein of kDa and efflux of cholesterol and to (18Klucken J. Buchler C. Orso E. Kaminski W.E. Porsch-Ozcurumez M. Liebisch G. Kapinsky M. Diederich W. Drobnik W. Dean M. Allikmets R. Schmitz G. Proc. Natl. S. A. 2000; PubMed Scopus Google Scholar). the from G. T. 2001; PubMed Scopus Google Scholar). The mammalian ABCG1 cDNA was identified from studies and RNA from either a murine cell (10Savary S. Denizot F. Luciani M. Mattei M. Chimini G. Mamm. Genome. 1996; 7: 673-676Crossref PubMed Scopus (52) Google a murine cell J.M. Tiller G.E. Fletcher J.A. Lux M.L. Raab E. Goldenson D. Son D. Arciniegas S. Wu R.L. Gene (Amst.). 1997; 185: 77-85Crossref PubMed Scopus (78) Google or a human J.M. Tiller G.E. Fletcher J.A. Lux M.L. Raab E. Goldenson D. Son D. Arciniegas S. Wu R.L. Gene (Amst.). 1997; 185: 77-85Crossref PubMed Scopus (78) Google Scholar) or and a human cDNA C. A. A. G. J. Hum. Genet. 1996; Google Scholar). murine and human cDNAs and identity at the amino acid and acid In high expression of ABCG1 mRNA was in and brain, expression in and was or (10Savary S. Denizot F. Luciani M. Mattei M. Chimini G. Mamm. Genome. 1996; 7: 673-676Crossref PubMed Scopus (52) Google Scholar, 11Croop J.M. Tiller G.E. Fletcher J.A. Lux M.L. Raab E. Goldenson D. Son D. Arciniegas S. Wu R.L. Gene (Amst.). 1997; 185: 77-85Crossref PubMed Scopus (78) Google Scholar). studies that murine ABCG1 mRNA levels were induced were either with LXR or were to cholesterol cells (18Klucken J. Buchler C. Orso E. Kaminski W.E. Porsch-Ozcurumez M. Liebisch G. Kapinsky M. Diederich W. Drobnik W. Dean M. Allikmets R. Schmitz G. Proc. Natl. S. A. 2000; PubMed Scopus Google Scholar, A. J.M. A. P.A. J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar, R. D. A.J. Proc. Natl. S. A. 2002; PubMed Scopus Google Scholar). and identified multiple human ABCG1 transcripts that are as a of at exons and alternative mRNA splicing T. Porsch-Ozcurumez M. Klucken J. Schmitz G. Biochim. Biophys. Acta. 2000; PubMed Scopus Google Scholar, S. S. T. E. G. Biophys. Res. 2001; PubMed Scopus Google Scholar, A. I. J. P.A. J. Biol. Chem. 2001; 276: Full Text Full Text PDF PubMed Scopus Google Scholar). of the mRNAs has a unique of exons C. A. A. G. J. Hum. Genet. 1996; Google Scholar, A. I. J. P.A. J. Biol. Chem. 2001; 276: Full Text Full Text PDF PubMed Scopus Google Scholar, T. Klucken J. M. Liebisch G. Luciani M.F. Chimini G. Kaminski W.E. Schmitz G. Biophys. Res. 1999; PubMed Scopus Google Scholar). unique contains an in the of multiple putative protein isoforms that contain amino of amino and a amino at their carboxyl S. S. T. E. G. Biophys. Res. 2001; PubMed Scopus Google Scholar, A. I. J. P.A. J. Biol. Chem. 2001; 276: Full Text Full Text PDF PubMed Scopus Google Scholar). A. and A. is such at the amino terminus protein or In to the multiple human a single murine ABCG1 cDNA has been identified to The LXR response PubMed Scopus Google Scholar) that is to be for the of the murine gene by has to be identified. In the the of exons and mRNAs that encode three putative ABCG1 protein isoforms. In multiple an intron of the Abcg1 studies suggest that these are and to the gene in numerous tissues in response to LXR In situ hybridization studies that ABCG1 is expressed at relatively high levels in the olfactory epithelium, hind brain, eye, and dorsal root of embryos and/or that each ABCG1 the efflux of cholesterol to suggest that ABCG1 may a role in efflux from and cells in addition to macrophages. expression for and were from was from LXR ligand PubMed Scopus Google Scholar) was from and ligand M.F. E. J. Chem. 1994; PubMed Scopus Google Scholar) was a from was from was by of human were from and or with T0901317. to were with their to that were used in electrophoretic mobility shift or to of the and used for are in I. The of was used in this in a Cell of and cells were as P.A. J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). the of two of either or were by and the into Mol. Cell. Biol. PubMed Scopus Google Scholar). transfection of cells was in in as P.A. J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar, Y. T. P.A. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). and were with either expression and/or of cells were with and or for to cell and of P.A. J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). were for small in transfection following the of P.A. J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). Hek293 cells were in and in and to We used to of Hek293 cells with the or the containing a cDNA encoding a specific ABCG1 of cells with plasmids encoding protein and that the transfection was transfection of Hek293 cells with the the cells were with and for in with an 2 W. Dean Biol. 15: PubMed Scopus Google and and The cells were with and for an additional in and and this the cells were more with and for an additional in or in with either or were and at for 2 and the in the as A. P.A. P.A. Proc. Natl. S. A. 2000; PubMed Scopus Google Scholar). was to each to were and the A. P.A. P.A. Proc. Natl. S. A. 2000; PubMed Scopus Google Scholar). efflux was by the of the by the of the in the cells and was for was cDNA from to the containing to two and was to the of the was with a gene specific corresponding to exon of the mouse gene and following for of for for for 2 and 15 of for for for 2 at for The were and an was used as for with and the following for of for for for 2 of for for for 2 of for for for 2 at for The were and were into for of were as P.A. C. P.A. J. Biol. Chem. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar). of was into to the were and at were to for in containing The was with with and were with either and or for by RNA RNA and RNA was was as Y. P.A. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). The of the and are in I. were at the with and at the with were as P.A. J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). and were in the B. S. P.A. J. Biol. Chem. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar). In of situ hybridization was as R. F. E. the Press, Scholar). a corresponding to of the and of the of the murine ABCG1 was into to The was with either or RNA the to or in situ embryos were at embryonic day and in in at in situ hybridization of embryos were at embryonic day or embryonic day in and at the were with the for at to addition of The in for to for Identification of ABCG1 single murine ABCG1 cDNA was reported by et al. and et al. (10Savary S. Denizot F. Luciani M. Mattei M. Chimini G. Mamm. Genome. 1996; 7: 673-676Crossref PubMed Scopus (52) Google Scholar, 11Croop J.M. Tiller G.E. Fletcher J.A. Lux M.L. Raab E. Goldenson D. Son D. Arciniegas S. Wu R.L. Gene (Amst.). 1997; 185: 77-85Crossref PubMed Scopus (78) Google Scholar). to this corresponding to exons and as To determine additional murine ABCG1 transcripts are used to cDNAs from multiple tissues. The in and cDNAs that a unique at the cDNAs were used as for corresponding to the and to exon were corresponding to the and exon and the were and with identity to exons 1, and and to However, one from the a of exon of the with that were in two exons and in that were of exon The containing corresponding to exons is referred to as RNA as a to cDNA to exon 15 and either exon or exon As this in the of cDNAs corresponding to and a cDNA was that to a containing exon to exons in The of these three transcripts are in studies (10Savary S. Denizot F. Luciani M. Mattei M. Chimini G. Mamm. Genome. 1996; 7: 673-676Crossref PubMed Scopus (52) Google Scholar, 11Croop J.M. Tiller G.E. Fletcher J.A. Lux M.L. Raab E. Goldenson D. Son D. Arciniegas S. Wu R.L. Gene (Amst.). 1997; 185: 77-85Crossref PubMed Scopus (78) Google Scholar) identified an in exon of the 1, and at this would a protein containing amino In contrast, and exon 1, contain an in exon at this would proteins containing either or amino proteins from of the three mRNAs are to contain an carboxyl terminus of amino by exons to differ at their amino 1, and of and ABCG1 studies of murine and human to studies and exon 1, and The a high of the and amino acid of exons and of the murine gene and exons and of the human gene However, corresponding to the murine exons and were identified in human or human RNA with corresponding to murine exons and at human cDNAs and corresponding to murine exons and In to human transcripts that corresponding to murine exons or that and to murine transcripts that to human exons and The murine exons of and The of the murine Abcg1 gene are in R. Annu. Rev. PubMed Scopus Google of the murine ABCG1 exons and in a and of ABCG1 in studies have that ABCG1 expression is induced are with the LXR ligand A. P.A. P.A. Proc. Natl. S. A. 2000; PubMed Scopus Google Scholar). To the expression and of ABCG1 transcripts in vivo normal or with for to RNA was used to determine the expression and of ABCG1 transcripts and that contain the or the individual transcripts or To date, have been to a specific for The of that with induced ABCG1 transcripts in tissues with the of the murine as a The a of expression and induction in response to with In contrast, the from that the mRNA was to the and However, mRNA levels were induced following with the LXR ligand levels of and mRNAs must be expressed in a of murine tissues (i) the was identified in cDNA from the and and (ii) RNA from a of cDNAs corresponding to and of ABCG1 determine the of expression of murine ABCG1 mRNA in tissues and cell in situ hybridization studies a corresponding to the of murine ABCG1 mRNA to ABCG1 the of in situ hybridization the ABCG1 identified transcripts in the hind brain, dorsal root and of embryonic day embryos from and The no In an attempt to the expression of ABCG1, were a with for of embryonic day the hind brain more the of by with To that the containing for or and RNA from embryonic day and embryonic day embryos that of induced ABCG1 levels in the of the and induced ABCG1 and mRNA levels in embryonic day and embryonic day embryos these that the LXR the and is to the In situ hybridization is a and the of a of in tissues is no embryos were at embryonic day was to day of a We that these The of that ABCG1 is expressed in the murine eye and is induced in response to T0901317. the Drosophila white the putative of mammalian ABCG1, is expressed in the eye, this the that ABCG1 and white have in this The of and that ABCG1 transcripts are expressed in the To the of from embryonic day and embryonic day that high levels of ABCG1 transcripts are in the olfactory epithelium, and neuronal and expression was in the cells of the the of the hind brain and and and in dorsal root The was specific many the liver and no was the was with the of the and the expression of ABCG1 is in The of that ABCG1 transcripts are expressed in the murine eye, and the levels are induced following of in the Identification and of of the ABCG1 with A. J.M. A. P.A. J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar, R. D. A.J. Proc. Natl. S. A. 2002; PubMed Scopus Google Scholar, Proc. Natl. S. A. 2001; PubMed Scopus Google Scholar, J. D. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google that murine Abcg1 gene expression is induced in response to for To that are for such gene used the in the of to of the murine identified seven putative that of to the of that corresponding to each putative murine ABCG1 from the human Abcg1 gene A. I. J. P.A. J. Biol. Chem. 2001; 276: Full Text Full Text PDF PubMed Scopus Google Scholar) was in each The demonstrate that and form with and form a relatively In the of LXR and RXR, these four were in the of to was the was with corresponding to or To further the that a corresponding to was in the of LXR and and in the and or of of or The studies demonstrate that and have for than In the of the to function as a in the that the of to the is The from suggest that and may transcription of the Abcg1 To this two of either or were to a was into cells in the or of plasmids encoding and and the cells were for in the or of for LXR and/or The of that the of two of either or were induced the cells were with and/or We that these are in the of the Abcg1 In cells were with a gene the of of of exon and the of exon gene was However, no additional was the cells were with plasmids encoding LXR and and in the of that the of exon contain an ABCG1 to determine individual ABCG1 isoforms the efflux of to the in Hek293 cells were with an or a a specific ABCG1 and in the of for The efflux of cholesterol to or with either or was a The that transfection of cholesterol efflux to or and The demonstrate that each ABCG1 was in cholesterol efflux to in cells and in cells that been with to LXR further in cholesterol efflux was following transfection of cells with two ABCG1 isoforms two exons exons and and transcripts and that encode two putative murine ABCG1 isoforms the fact that ABCG1 transcripts are at either exon or exon and that these exons are by that the mouse Abcg1 gene contains two that mRNA levels were induced were with or or for LXR (18Klucken J. Buchler C. Orso E. Kaminski W.E. Porsch-Ozcurumez M. Liebisch G. Kapinsky M. Diederich W. Drobnik W. Dean M. Allikmets R. Schmitz G. Proc. Natl. S. A. 2000; PubMed Scopus Google Scholar, A. J.M. A. P.A. J. Biol. Chem. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar, R. D. A.J. Proc. Natl. S. A. 2002; PubMed Scopus Google Scholar). We now that the is induced by LXR that are to In the and to and functional that are in transcription of the gene in response to LXR these are exons 2 and in of of exon of the murine gene to additional putative that these four the expression of ABCG1 transcripts in response to LXR However, the that these are downstream of exon to to this The studies that each murine is of cholesterol efflux to The are consistent with that cholesterol or efflux to following of ABCG1 mRNA levels of cells with either (18Klucken J. Buchler C. Orso E. Kaminski W.E. Porsch-Ozcurumez M. Liebisch G. Kapinsky M. Diederich W. Drobnik W. Dean M. Allikmets R. Schmitz G. Proc. Natl. S. A. 2000; PubMed Scopus Google Scholar) or D. W. F. Proc. Natl. S. A. PubMed Scopus Google Scholar). are in with et al. D. W. F. Proc. Natl. S. A. PubMed Scopus Google reported that cholesterol efflux to was stimulated following of ABCG1 the However, the studies demonstrate that ABCG1 isoforms cholesterol The that cholesterol efflux was stimulated following of single ABCG1 isoforms suggest that each dimerizes to form functional studies be to determine ABCG1 isoforms with half transporters in ABC ABCG5, ABCG8, and are that are in efflux and are by ABCG1, is expressed in multiple tissues A. A. R. E. 2002; PubMed Scopus Google Scholar) studies have that is for the efflux of cholesterol to that and J. Lipid Res. 2001; 42: Full Text Full Text PDF PubMed Google Scholar). In contrast, ABCG1 the efflux of cholesterol to HDL, than to (18Klucken J. Buchler C. Orso E. Kaminski W.E. Porsch-Ozcurumez M. Liebisch G. Kapinsky M. Diederich W. Drobnik W. Dean M. Allikmets R. Schmitz G. Proc. Natl. S. A. 2000; PubMed Scopus Google Scholar, D. W. F. Proc. Natl. S. A. PubMed Scopus Google Scholar) the importance of ABCG1 and in cholesterol efflux in vivo is to the of and and the expression of these two the that the expression of ABCG1 and in and cells M. M. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar) that these two transporters may have in In to ABCG1 and high expression of and is limited to and to of the small C. J.A. J. Biol. Chem. 2002; Full Text Full Text PDF PubMed Scopus Google Scholar). The heterodimers the efflux of from into the and of cholesterol and from the J. D. Proc. Natl. S. A. 2002; PubMed Scopus Google Scholar, J. J. 2002; PubMed Scopus Google Scholar). However, in to studies with ABCG1 and no has been identified to that in either or in a with cholesterol and and of in the and tissues J. B. R. 2000; PubMed Scopus Google Scholar, S. S. Allikmets R. R. G. Dean M. Genet. 2001; PubMed Scopus Google Scholar). In contrast, mutations in in levels M. Orso E. Klucken J. T. A. Diederich W. Drobnik W. S. Buchler C. Porsch-Ozcurumez M. Kaminski W.E. G. C. Schmitz G. Genet. 1999; PubMed Scopus Google Scholar, A. M. S.M. M. C. J.A. S. S. M. D. J. B. S. Genet. 1999; PubMed Scopus Google Scholar, S. M. J. G. Genet. 1999; PubMed Scopus Google Scholar). The of Abcg1 and would to the role of ABCG1 in and to of its role to of ABC Drosophila white form two heterodimers or that transport substrates into the pigment granule of the fly eye (12Mackenzie S.M. Howells A.J. Cox G.B. Ewart G.D. Genetica (Dordrecht). 2000; 108: 239-252Crossref PubMed Scopus (92) Google Scholar). and J. 2001; PubMed Scopus Google Scholar) that were to and that Drosophila white was in neuronal function in the fly brain by a that is of these suggest that Drosophila white dimerize with to in the eye and that has a role in neuronal in the fly these with Drosophila white and the that that murine ABCG1 mRNA is expressed in the hind brain, dorsal root Mol. 2002; PubMed Scopus Google M. A. G. and A. and and the cells that the suggest that ABCG1 may neuronal and We for the in situ