Abstract
LXR and PPAR receptors belong to the nuclear receptor superfamily of transcriptional activating factors. Using ligand-dependent transcription assays, we found that 5-tetradecyloxy-2-furancarboxylic acid (TOFA) transactivates chimeric receptors composed of the glucocorticoid receptor DNA binding domain and the ligand binding regions of PPARalpha, PPARbeta (NUC-1) and LXRbeta (NER) receptors. In the same assays, ligands for PPARs (oleic acid, WY-14643 and L-631,033) and LXRs (hydroxycholesterols) maintain their respective receptor selectivity. TOFA and hydroxycholesterols also stimulate transcription from a minimal fibrinogen promoter that is under the control of AP-1 or NF-kappaB transcription factor binding sites. In addition to their effects on transcription, these LXRbeta activators induce neuronal differentiation in rat pheochromocytoma cells. TOFA and the natural LXR agonist, 22 (R)-hydroxycholesterol, stimulate neurite outgrowth in 55 and 28% of cells, respectively. No neurite outgrowth was induced by the related 22(S)-hydroxycholesterol, which does not activate the LXR family. These results suggest that the hydroxycholesterol signaling pathway has a complex effect on transcription that mediates the activity of TOFA and hydroxycholesterol on neuronal differentiation in pheochromocytoma cells.
MeSH terms
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Animals
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Anticholesteremic Agents / pharmacology
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COS Cells
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Cell Differentiation / drug effects
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Cell Line
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Cholesterol / pharmacology
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DNA-Binding Proteins
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Furans / pharmacology*
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Hypolipidemic Agents / pharmacology
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Liver X Receptors
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Nerve Growth Factors / pharmacology
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Neurons / cytology
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Neurons / drug effects
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Neurons / physiology*
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Oleic Acid / pharmacology
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Orphan Nuclear Receptors
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Peroxisome Proliferators / pharmacology
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Pyrimidines / pharmacology
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Rats
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Receptors, Cytoplasmic and Nuclear / drug effects
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Receptors, Cytoplasmic and Nuclear / physiology*
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Receptors, Glucocorticoid / drug effects
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Receptors, Glucocorticoid / physiology
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Recombinant Fusion Proteins / drug effects
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Recombinant Fusion Proteins / metabolism
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Trans-Activators / metabolism
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Transcription Factors / drug effects
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Transcription Factors / physiology
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Transcription, Genetic / drug effects*
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Transcriptional Activation / drug effects
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Transfection
Substances
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Anticholesteremic Agents
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DNA-Binding Proteins
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Furans
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Hypolipidemic Agents
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Liver X Receptors
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Nerve Growth Factors
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Orphan Nuclear Receptors
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Peroxisome Proliferators
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Pyrimidines
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Receptors, Cytoplasmic and Nuclear
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Receptors, Glucocorticoid
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Recombinant Fusion Proteins
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Trans-Activators
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Transcription Factors
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Oleic Acid
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5-(tetradecyloxy)-2-furancarboxylic acid
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pirinixic acid
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Cholesterol