Abstract
Initial step toward the reverse-cholesterol transport is cholesterol efflux that is mediated by the ATP-binding cassette transporter A1 (ABCA1). However, it is unknown how the cholesteryl ester (CE) hydrolysis induces the expression of the ABCA1 gene. Overexpression of hormone-sensitive lipase (HSL) increased the hydrolysis of CE and stimulated the expression of ABCA1 gene at the transcriptional level in RAW 264.7 macrophages. The stimulatory effects of the HSL overexpression and cholesterol loading on the ABCA1 promoter activity were additive. Mutational analyses of the promoter of ABCA1 identified the responsible element as the direct repeat-4 (DR-4) that binds LXR/RXR heterodimers. In conclusion, stimulation of hydrolysis of CE in macrophages induces the expression of ABCA1 gene primarily via the LXR-dependent pathway and can be useful for the prevention of atherosclerosis.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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ATP Binding Cassette Transporter 1
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ATP-Binding Cassette Transporters / genetics*
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Animals
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Atherosclerosis / genetics
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Atherosclerosis / prevention & control
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Cholesterol / metabolism
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Cholesterol Esters / metabolism
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DNA Mutational Analysis
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DNA-Binding Proteins / metabolism
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Dimerization
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Humans
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Hydrolysis
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Liver X Receptors
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Macrophages, Peritoneal / enzymology*
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Mice
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Orphan Nuclear Receptors
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Promoter Regions, Genetic
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Receptors, Cytoplasmic and Nuclear / metabolism
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Retinoid X Receptors / metabolism
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Sterol Esterase / biosynthesis*
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Transcriptional Activation*
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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Cholesterol Esters
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DNA-Binding Proteins
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Liver X Receptors
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Orphan Nuclear Receptors
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Receptors, Cytoplasmic and Nuclear
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Retinoid X Receptors
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Cholesterol
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Sterol Esterase