Sterol-dependent Transactivation of theABC1 Promoter by the Liver X Receptor/Retinoid X Receptor

Tangier disease, a condition characterized by low levels of high density lipoprotein and cholesterol accumulation in macrophages, is caused by mutations in the ATP-binding cassette transporter ABC1. In cultured macrophages, ABC1 mRNA was induced in an additive fashion by 22(R)-hydroxycholesterol and 9-cis-retinoic acid (9CRA), suggesting induction by nuclear hormone receptors of the liver X receptor (LXR) and retinoid X receptor (RXR) family. We cloned the 5′-end of the human ABC1 transcript from cholesterol-loaded THP1 macrophages. When transfected into RAW macrophages, the upstream promoter was induced 7-fold by 22(R)-hydroxycholesterol, 8-fold by 9CRA, and 37-fold by 9CRA and 22(R)-hydroxycholesterol. Furthermore, promoter activity was increased in a sterol-responsive fashion when cotransfected with LXRα/RXR or LXRβ/RXR. Further experiments identified a direct repeat spaced by four nucleotides (from −70 to −55 base pairs) as a binding site for LXRα/RXR or LXRβ/RXR. Mutations in this element abolished the sterol-mediated activation of the promoter. The results show sterol-dependent transactivation of the ABC1 promoter by LXR/RXR and suggest that small molecule agonists of LXR could be useful drugs to reverse foam cell formation and atherogenesis. Tangier disease, a condition characterized by low levels of high density lipoprotein and cholesterol accumulation in macrophages, is caused by mutations in the ATP-binding cassette transporter ABC1. In cultured macrophages, ABC1 mRNA was induced in an additive fashion by 22(R)-hydroxycholesterol and 9-cis-retinoic acid (9CRA), suggesting induction by nuclear hormone receptors of the liver X receptor (LXR) and retinoid X receptor (RXR) family. We cloned the 5′-end of the human ABC1 transcript from cholesterol-loaded THP1 macrophages. When transfected into RAW macrophages, the upstream promoter was induced 7-fold by 22(R)-hydroxycholesterol, 8-fold by 9CRA, and 37-fold by 9CRA and 22(R)-hydroxycholesterol. Furthermore, promoter activity was increased in a sterol-responsive fashion when cotransfected with LXRα/RXR or LXRβ/RXR. Further experiments identified a direct repeat spaced by four nucleotides (from −70 to −55 base pairs) as a binding site for LXRα/RXR or LXRβ/RXR. Mutations in this element abolished the sterol-mediated activation of the promoter. The results show sterol-dependent transactivation of the ABC1 promoter by LXR/RXR and suggest that small molecule agonists of LXR could be useful drugs to reverse foam cell formation and atherogenesis. high density lipoprotein 9-cis-retinoic acid 22(R)-hydroxycholesterol 25-hydroxycholesterol 7-ketocholesterol liver X receptor retinoid X receptor cotransfected mixture of two receptors putative heterodimer complex steroidogenic factor 1 cholesterol ester transfer protein direct repeat rapid amplification of cDNA ends base pair(s) polymerase chain reaction low density lipoprotein Plasma HDL1-cholesterol levels are inversely related to the incidence of coronary artery disease (1Castelli W.P. Garrison R.J. Wilson P.W. Abbott R.D. Kalousdian S. Kannel W.B. J. Am. Med. Assoc. 1986; 256: 2835-2838Crossref PubMed Scopus (2091) Google Scholar). Two genetic diseases illustrate this phenomenon, the rare Tangier disease and the more common familial HDL deficiency. Tangier disease is characterized by an extremely low concentration of circulating HDL and the accumulation of cholesteryl esters in tonsils, liver, spleen, and intestinal mucosa, mostly in macrophage foam cells (2Serfaty-Lacrosniere C. Civeira F. Lanzberg A. Isaia P. Berg J. Janus E.D. Smith Jr., M.P. Pritchard P.H. Frohlich J. Lees R.S. Barnard G.F. Ordovas J.M. Schaefer E.J. Atherosclerosis. 1994; 107: 85-98Abstract Full Text PDF PubMed Scopus (216) Google Scholar). Patients with familial HDL deficiency exhibit a low concentration of HDL particles and an increased risk of coronary artery disease (3Marcil M. Brooks-Wilson A. Clee S.M. Roomp K. Zhang L.H., Yu, L. Collins J.A. van Dam M. Molhuizen H.O. Loubster O. Ouellette B.F. Sensen C.W. Fichter K. Mott S. Denis M. Boucher B. Pimstone S. Genest Jr., J. Kastelein J.J. Hayden M.R. Lancet. 1999; 354: 1341-1346Abstract Full Text Full Text PDF PubMed Scopus (322) Google Scholar). 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Duverger N. Funke H. Assman G. Dinger M. Dean M. Chimini G. Santamarina-Fojo S. Fredrickson D.S. Denefle P. Brewer Jr., H.B. Proc. Natl. Acad. Sci. U. S. A. 1999; 96: 12685-12690Crossref PubMed Scopus (230) Google Scholar, 16Brousseau M.E. Schaefer E.J. Dupuis J. Eustace B. Van Eerdewegh P. Goldkamp A.L. Thurston L.M. FitzGerald M.G. Yasek-McKenna D. O'Neill G. Eberhart G.P. Weiffenbach B. Ordovas J.M. Freeman M.W. Brown Jr., R.H. Gu J.Z. J. Lipid Res. 2000; 41: 433-441Abstract Full Text Full Text PDF PubMed Google Scholar, 20Luciani M.F. Denizot F. Savary S. Mattei M.G. Chimini G. Genomics. 1994; 21: 150-159Crossref PubMed Scopus (231) Google Scholar). Whereas its expression is ubiquitous, the highest levels of human or murine mRNAs were found in placenta, fetal tissues, liver, lung, and adrenal glands (21Langmann T. Klucken J. Reil M. Liebisch G. Luciani M.F. Chimini G. Kaminski W.E. Schmitz G. Biochem. Biophys. Res. 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PubMed Scopus Google Scholar). the of the hABC1 promoter and show that this promoter is active in macrophages and that its sterol-mediated activation the binding of to a was with the cDNA 1 of mRNA from and cells that were into macrophage with and to acetylated for reverse reverse a first and was the reverse A second and was of the first with the The were by The of the human was with a to nucleotides of the Two were that were positive by for 1 and by a was by with the were cloned in A for J. T. A Scholar) to positive for promoter and both that cloned from The of are in the of human contains exons and The cell were from The murine RAW and human or cell were in with fetal and cells were in containing fetal and with cells were with in macrophages were from as J.M. S.D. Proc. Natl. Acad. Sci. U. S. A. 93: PubMed Scopus Google Scholar). were in with experiments in and or activation experiments in RAW and to the activation a of of DNA and of well were transactivation of and of receptor was to a of of DNA The transfected cells were cultured in in the presence of and or of 22(R)-hydroxycholesterol 25-hydroxycholesterol or 7-ketocholesterol acid or for The were the A to the activity of the hABC1 promoter was by a of the hABC1 promoter (from to into the A promoter (from to was by of this were by from to or The of the were S.D. were to of LXR and LXR in cell transactivation by LXR/RXR of the hABC1 promoter is cells were and cultured as and A was with of for cell were of specific for and as an cells were transfected with the (from to or a containing of a sterol-responsive element of the promoter Y. Tall A.R. J. Clin. Invest. 2000; 105: 513-520Crossref PubMed Scopus (309) Google Scholar). These were cotransfected with gene and as The cells were with or 9CRA in fetal with The results experiments in for the promoter and experiments in for the the promoter. cells were transfected and to the in experiments in were S.D. of is by of were by or amplification of the hABC1 promoter. The results two experiments of S.D. of is by of promoter containing the element that was identified as a binding site for LXR/RXR or a were and to or with and nuclear from cells transfected with or were with for or or with a different experiments were with The the of the of cells were transfected with hABC1 promoter (from to or its The mutations are in The results two experiments of S.D. of is by was with were as J. T. A Scholar). A human ABC1 to exons of the was by reverse the and the reverse LXR were from and K. R.M. R.A. Mangelsdorf D.J. 1995; PubMed Scopus Google Scholar, W. 1995; PubMed Google Scholar). A was as an and reverse were with were to were as Y. Tall A.R. J. Clin. Invest. 2000; 105: 513-520Crossref PubMed Scopus (309) Google Scholar). were from cells cotransfected with and or and containing the element or its were with and at a concentration of or to a was to to the from and were from the gene be activated by oxysterols acid in macrophages, of from human macrophages. a of ABC1 mRNA in cells with or 9CRA additive effect was with when with These suggest activation of by LXR/RXR B.A. Mangelsdorf D.J. PubMed Scopus Google Scholar). the promoter of the human ABC1 mRNA from cholesterol-loaded macrophages and cells In macrophages this a major transcript of a first of by a second of to 1 This is by the human exons and (21Langmann T. Klucken J. Reil M. Liebisch G. Luciani M.F. Chimini G. Kaminski W.E. Schmitz G. Biochem. Biophys. Res. Commun. 1999; 257: 29-33Crossref PubMed Scopus (429) Google Scholar). In different a of found in cells the by the exons and (21Langmann T. Klucken J. Reil M. Liebisch G. Luciani M.F. Chimini G. Kaminski W.E. Schmitz G. Biochem. Biophys. Res. Commun. 1999; 257: 29-33Crossref PubMed Scopus (429) Google Scholar). contains of upstream of the is different from the exons found in THP1 has the as transcript the A of the of exons exons with of the human A of the from the the and a of a at and a of an A at of the two in with the in (14Remaley A.T. Rust S. Rosier M. Knapper C. Naudin L. Broccardo C. Peterson K.M. Koch C. Arnould I. Prades C. Duverger N. Funke H. Assman G. Dinger M. Dean M. Chimini G. Santamarina-Fojo S. Fredrickson D.S. Denefle P. Brewer Jr., H.B. Proc. Natl. Acad. Sci. U. S. A. 1999; 96: 12685-12690Crossref PubMed Scopus (230) Google Scholar) a and In the of the transcript of THP1 a in in an amino acids at the amino In the of a at the of be in transcript and transcript the This results in an acid for transcript C. A of the putative amino acid of ABC1 with to the of two of the ABC1 with and with This that the of hABC1 is The promoter upstream of 1 was to when transfected into cells the upstream of transcript was the a of DNA with a of 1 cloned from the human A is at and an site at of this factor binding the of the transfected the RAW cell with a for activation by a of J.M. J.L. J. Biol. Chem. 1997; Full Text Full Text PDF PubMed Scopus Google Scholar) a of D.S. Syka P.M. Lazarchik S.B. Mangelsdorf D.J. Parker K.L. R.A. Proc. Natl. Acad. Sci. U. S. A. 1997; PubMed Scopus Google Scholar) and 9CRA, to with transfected cells with or 9CRA and 8-fold promoter When both were was a 37-fold induction A response was with promoter containing or of upstream the response of the ABC1 promoter to different We the transfected cells with is a of and a of LXR D.S. Syka P.M. Lazarchik S.B. Mangelsdorf D.J. Parker K.L. R.A. Proc. Natl. Acad. Sci. U. S. A. 1997; PubMed Scopus Google Scholar). were with is in human foam cells L.M. H. U. I. M. Y. G. O. J. Clin. Invest. 97: PubMed Google Scholar). is a of the hABC1 promoter with effect of was when in with 9CRA, a additive effect was for when with 9CRA This of sterol is with a the role of and in the sterol-mediated up-regulation of that the mRNA of nuclear receptors was in cells We their expression in macrophages from Both receptors were in macrophages by of with a much for We two cell for transactivation and in both and could be in cells in the of mRNA for are low in cells and to transactivation experiments in cell the of in the sterol up-regulation of cotransfected cells with the human ABC1 promoter and with receptors We the promoter was sterol-responsive in macrophages In cells cotransfected up-regulation of the promoter by and 9CRA The of 9CRA and in an additive effect activity was increased when were as was the sterol was effect by 9CRA or 9CRA and of caused a in expression and a effect of 9CRA and induction with and induction with 9CRA a positive for experiments a containing of the binding site of promoter Y. Tall A.R. J. Clin. Invest. 2000; 105: 513-520Crossref PubMed Scopus (309) Google Scholar) in the of transfected this was and in cells and in and an additive or effect was with LXR in increased activity and increased induction by 9CRA in activity with These results suggest that in cells a role in the response of and with a in sterol-dependent promoter activity when LXR and are In cells a of the was transfected receptors with or increased the activity of the promoter and both to in increased transactivation of the promoter and with the with the of the hABC1 promoter involved in its sterol-mediated activation results to with of the promoter from or to of (from to the the response to and 9CRA was of and the activity and abolished the response to sterol the to contains an element the −70 and −55 the that the element is for sterol a of this element in the of the hABC1 promoter (from to Both were by nucleotides from the nuclear hormone binding as in This the expression the activity was the abolished the response to or in with the element containing the or the in the to nuclear from cells cotransfected with or When the hABC1 element is a major in activity is for both of nuclear with of the is to with the the of the is for factor In cells cotransfected with the or common and binding activity and In cells cotransfected with to LXR and that the a complex Y. Tall A.R. J. Clin. Invest. 2000; 105: 513-520Crossref PubMed Scopus (309) Google Scholar). specific for a effect as These results show that or this In this identified a of the is active in macrophages and is induced by 22(R)-hydroxycholesterol and 9-cis-retinoic of the major transcript in cholesterol-loaded THP1 macrophages to the of this promoter and that of the upstream in the cDNA (21Langmann T. Klucken J. Reil M. Liebisch G. Luciani M.F. Chimini G. Kaminski W.E. Schmitz G. Biochem. Biophys. Res. Commun. 1999; 257: 29-33Crossref PubMed Scopus (429) Google Scholar) are to the or to a element in the hABC1 promoter and its activation by and LXR agonists could be useful drugs to reverse foam cell formation and atherogenesis. A element the sterol up-regulation of gene and that this is the site identified Y. Tall A.R. J. Clin. Invest. 2000; 105: 513-520Crossref PubMed Scopus (309) Google Scholar, J.M. J.L. J. Biol. Chem. 1997; Full Text Full Text PDF PubMed Scopus Google Scholar), the element in the ABC1 promoter is found in an the The of this element its high Mutations in the in a of the expression of the activity is A activation of the promoter by 9CRA the presence of binding site for the element identified is for the sterol-mediated activation of the hABC1 promoter The of activation of the ABC1 promoter by that its expression be in is in and in foam cells L.M. H. U. I. M. Y. G. O. J. Clin. Invest. 97: PubMed Google Scholar) and is a of promoter in foam is a of LXR B.A. Mangelsdorf D.J. PubMed Scopus Google Scholar, J.M. J.L. J. Biol. Chem. 1997; Full Text Full Text PDF PubMed Scopus Google Scholar). the accumulation of oxysterols in in activation of This that small that are LXR be drugs at foam cell formation and that be useful as a for The activation of the by 9CRA is increased when with This that with to the induction of ABC1 by an foam cell could be to a more by of for The of to for the of in (24Peet D.J. Turley S.D. Ma W. Janowski B.A. Lobaccaro J.M. Hammer R.E. Mangelsdorf D.J. Cell. 1998; 93: 693-704Abstract Full Text Full Text PDF PubMed Scopus (1252) Google Scholar) that receptors different In both and are to hABC1 or Y. Tall A.R. J. Clin. Invest. 2000; 105: 513-520Crossref PubMed Scopus (309) Google Scholar), is more in the sterol response of hABC1 This is with the that to be more in macrophages that hABC1 is up-regulated at the by oxysterols and 9CRA LXR/RXR a element the These results for the that to the of reverse cholesterol transport Y. Tall A.R. J. Clin. Invest. 2000; 105: 513-520Crossref PubMed Scopus (309) Google Scholar). This to a of different of reverse cholesterol activity results in the of HDL into small particles and from HDL J. Biol. Chem. 1997; Full Text Full Text PDF PubMed Scopus Google Scholar). to be the for ABC1 J. 1999; PubMed Scopus Google Scholar, J.D. M. M. C. E. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). induction of and ABC1 by LXR/RXR to cholesterol efflux from macrophage foam