Regulation of ATP-binding cassette transporter A1 transcription by thyroid hormone receptor.
Transcriptional regulation of the ATP-binding cassette transporter (ABCA1) gene is complex. It involves multiple transcription start sites and the binding of several different transcription factors to the ABCA1 promoter region. Cholesterol- and oxysterol-mediated up-regulation of ABCA1 transcription includes the binding of the liver X receptor and retinoid X receptor (LXR/RXR) heterodimer to the DR-4 element of the ABCA1 promoter. In this study we show that another nuclear hormone receptor, thyroid hormone receptor (TR), can suppress ABCA1 transcription. Electrophoretic mobility shift assays using both purified proteins and isolated nuclear extracts from primary human fibroblasts and 293T cells demonstrate that the TR/RXR heterodimer is able to bind to the DR-4 element of the ABCA1 promoter. This binding is also demonstrated in vivo by chromatin immunoprecipitation studies. Luciferase assays from 293T cells transfected with TRbeta or LXRalpha expression plasmids show that TR, together with its ligand T3, suppresses ABCA1 transcriptional activity, even in the presence of LXR-activating oxysterols. Finally, competition between TR/RXR and LXR/RXR heterodimers to suppress or activate ABCA1 transcription is shown to be dynamic and dependent on the amount of nuclear receptor present in the cells. These data identify a novel regulatory mechanism for ABCA1 and suggest new strategies to modify its expression.
Huuskonen
Jarkko
J
Cardiovascular Research Institute, San Francisco, California 94143-0130, USA. jhuu6676@itsa.ucsf.edu
Vishnu
Meeta
M
Pullinger
Clive R
CR
Fielding
Phoebe E
PE
Fielding
Christopher J
CJ
D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism*; D000818:Animals; D001667:Binding, Competitive / Q000502:physiology; D002457:Cell Extracts / Q000235:genetics / Q000276:immunology; D002460:Cell Line; D002478:Cells, Cultured; D002645:Chickens; D002843:Chromatin / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000276:immunology / Q000378:metabolism; D024202:Electrophoretic Mobility Shift Assay; D005347:Fibroblasts / Q000276:immunology / Q000378:metabolism; D006801:Humans; D000071518:Liver X Receptors; D009687:Nuclear Proteins / Q000276:immunology / Q000378:metabolism; D057093:Orphan Nuclear Receptors; D011233:Precipitin Tests; D018160:Receptors, Cytoplasmic and Nuclear / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D011988:Receptors, Thyroid Hormone / Q000096:biosynthesis / Q000502:physiology*; D012091:Repetitive Sequences, Nucleic Acid; D012097:Repressor Proteins / Q000096:biosynthesis / Q000502:physiology*; D014158:Transcription, Genetic / Q000502:physiology*; D014162:Transfection
C577836:ABCA1 protein, human; D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D002457:Cell Extracts; D002843:Chromatin; D004268:DNA-Binding Proteins; D000071518:Liver X Receptors; C000605213:NR1H3 protein, human; D009687:Nuclear Proteins; D057093:Orphan Nuclear Receptors; D018160:Receptors, Cytoplasmic and Nuclear; D011988:Receptors, Thyroid Hormone; D012097:Repressor Proteins