Abstract
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 LXRalpha/RXR or LXRbeta/RXR. Further experiments identified a direct repeat spaced by four nucleotides (from -70 to -55 base pairs) as a binding site for LXRalpha/RXR or LXRbeta/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.
Publication types
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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ATP Binding Cassette Transporter 1
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ATP-Binding Cassette Transporters / chemistry
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ATP-Binding Cassette Transporters / genetics*
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Alitretinoin
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Amino Acid Sequence
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Animals
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Base Sequence
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Cell Line
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DNA-Binding Proteins
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Gene Library
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Glycoproteins / chemistry
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Glycoproteins / genetics*
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Humans
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Hydroxycholesterols / pharmacology
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Liver / metabolism
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Liver X Receptors
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Macrophages
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Molecular Sequence Data
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Orphan Nuclear Receptors
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Promoter Regions, Genetic*
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Receptors, Cytoplasmic and Nuclear / genetics
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Receptors, Cytoplasmic and Nuclear / metabolism*
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Receptors, Retinoic Acid / genetics
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Receptors, Retinoic Acid / metabolism*
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Recombinant Proteins / metabolism
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Retinoid X Receptors
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Sequence Alignment
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Sequence Homology, Amino Acid
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Sterols / pharmacology*
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Tangier Disease / genetics
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Transcription Factors / genetics
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Transcription Factors / metabolism*
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Transcription, Genetic
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Transcriptional Activation* / drug effects
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Transfection
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Tretinoin / pharmacology
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Tumor Cells, Cultured
Substances
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ABCA1 protein, human
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ATP Binding Cassette Transporter 1
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ATP-Binding Cassette Transporters
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DNA-Binding Proteins
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Glycoproteins
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Hydroxycholesterols
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Liver X Receptors
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NR1H3 protein, human
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Orphan Nuclear Receptors
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Receptors, Cytoplasmic and Nuclear
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Receptors, Retinoic Acid
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Recombinant Proteins
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Retinoid X Receptors
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Sterols
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Transcription Factors
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22-hydroxycholesterol
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Alitretinoin
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Tretinoin