Sterol-dependent transactivation of the ABC1 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 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.
Costet
P
P
Division of Molecular Medicine, Department of Medicine, Columbia University, New York, New York 10032, USA.
Luo
Y
Y
Wang
N
N
Tall
A R
AR
D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000737:chemistry / Q000235:genetics*; D000077556:Alitretinoin; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D004268:DNA-Binding Proteins; D015723:Gene Library; D006023:Glycoproteins / Q000737:chemistry / Q000235:genetics*; D006801:Humans; D006888:Hydroxycholesterols / Q000494:pharmacology; D008099:Liver / Q000378:metabolism; D000071518:Liver X Receptors; D008264:Macrophages; D008969:Molecular Sequence Data; D057093:Orphan Nuclear Receptors; D011401:Promoter Regions, Genetic; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism*; D018168:Receptors, Retinoic Acid / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D047488:Retinoid X Receptors; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D013261:Sterols / Q000494:pharmacology*; D013631:Tangier Disease / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D015533:Transcriptional Activation / Q000187:drug effects; D014162:Transfection; D014212:Tretinoin / Q000494:pharmacology; D014407:Tumor Cells, Cultured
C577836:ABCA1 protein, human; D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D004268:DNA-Binding Proteins; D006023:Glycoproteins; D006888:Hydroxycholesterols; D000071518:Liver X Receptors; C000605213:NR1H3 protein, human; D057093:Orphan Nuclear Receptors; D018160:Receptors, Cytoplasmic and Nuclear; D018168:Receptors, Retinoic Acid; D011994:Recombinant Proteins; D047488:Retinoid X Receptors; D013261:Sterols; D014157:Transcription Factors; C003585:22-hydroxycholesterol; D000077556:Alitretinoin; D014212:Tretinoin