Abstract
ATP-binding cassette transporter A1 (ABCA1) mediates an active efflux of cholesterol and phospholipids and is mutated in patients with Tangier disease. Expression of ABCA1 may be increased by certain oxysterols such as 22(R)-hydroxycholesterol via activation of the nuclear hormone receptor liver X receptor (LXR). In searching for potential modulators of ABCA1 expression, we have studied the effects of various mevalonate metabolites on the expression of ABCA1 in two human cell lines, THP-1 and Caco-2 cells. Most of the tested metabolites, including mevalonate, geranyl pyrophosphate, farnesyl pyrophosphate, and ubiquinone, failed to significantly change the expression levels of ABCA1. However, treatment with geranylgeranyl pyrophosphate resulted in a dose- and time-dependent reduction of ABCA1 expression. Geranylgeranyl pyrophosphate appears to reduce ABCA1 expression via two different mechanisms. One of these mechanisms is by acting directly as an antagonist of LXR since it reduces the interaction between LXR alpha or -beta with nuclear coactivator SRC-1. Another mechanism appears to involve activation of the Rho GTP-binding proteins since treatment of Caco-2 cells with inhibitors of geranylgeranyl transferase or the Rho proteins significantly increased the expression and promoter activity of ABCA1. Further studies showed that mutations in the DR4 element of the ABCA1 promoter completely eliminate the inducible activities of these inhibitors. These data indicate that activation of the Rho proteins may change the activation status of LXR.
MeSH terms
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ATP Binding Cassette Transporter 1
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ATP-Binding Cassette Transporters / genetics
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ATP-Binding Cassette Transporters / metabolism*
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Cell Line
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / metabolism
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Dose-Response Relationship, Drug
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Enzyme Inhibitors / pharmacology
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Gene Expression Regulation / drug effects*
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Gene Expression Regulation / physiology
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Histone Acetyltransferases
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Humans
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Hydroxycholesterols / pharmacology
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Interleukin-8 / genetics
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Interleukin-8 / metabolism
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Liver X Receptors
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Mevalonic Acid / metabolism
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Mutation
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Nuclear Receptor Coactivator 1
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Organic Chemicals*
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Orphan Nuclear Receptors
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Polyisoprenyl Phosphates / pharmacology*
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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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Receptors, Thyroid Hormone / genetics
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Receptors, Thyroid Hormone / metabolism*
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Recombinant Fusion Proteins / metabolism
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Tangier Disease / genetics
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Tangier Disease / metabolism
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Transcription Factors / metabolism*
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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Enzyme Inhibitors
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Hydroxycholesterols
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Interleukin-8
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L 839867
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Liver X Receptors
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NR1H3 protein, human
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Organic Chemicals
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Orphan Nuclear Receptors
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Polyisoprenyl Phosphates
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Receptors, Cytoplasmic and Nuclear
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Receptors, Retinoic Acid
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Receptors, Thyroid Hormone
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Recombinant Fusion Proteins
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Transcription Factors
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Histone Acetyltransferases
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NCOA1 protein, human
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Nuclear Receptor Coactivator 1
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geranylgeranyl pyrophosphate
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Mevalonic Acid