Transcription control and neuronal differentiation by agents that activate the LXR nuclear receptor family

• Published in: Molecular and cellular endocrinology 1999-09, Vol.155 (1), p.51-60
• Main Authors: Schmidt, Azriel, Vogel, Robert, Holloway, M.Katharine, Rutledge, Su Jane, Friedman, Oren, Yang, Zhelin, Rodan, Gideon A, Friedman, Eitan
• Format: Article
• Language: English
• Subjects: 5-tetradecyloxy-2-furancarboxylic acid; Animals; Anticholesteremic Agents - pharmacology; AP-1; Cell Differentiation - drug effects; Cell Line; Cholesterol - pharmacology; COS Cells; DNA-Binding Proteins; Furans - pharmacology; Hydroxycholesterols; Hypolipidemic Agents - pharmacology; Liver X Receptors; Nerve Growth Factors - pharmacology; Neurons - cytology; Neurons - drug effects; Neurons - physiology; NF-κB; Oleic Acid - pharmacology; Orphan Nuclear Receptors; Peroxisome Proliferators - pharmacology; Pheochromocytoma cells; PPAR; Pyrimidines - pharmacology; Rats; Receptors, Cytoplasmic and Nuclear - drug effects; Receptors, Cytoplasmic and Nuclear - physiology; Receptors, Glucocorticoid - drug effects; Receptors, Glucocorticoid - physiology; Recombinant Fusion Proteins - drug effects; Recombinant Fusion Proteins - metabolism; Trans-Activators - metabolism; Transcription Factors - drug effects; Transcription Factors - physiology; Transcription, Genetic - drug effects; Transcriptional Activation - drug effects; Transfection
• ISSN: 0303-7207; 1872-8057
• DOI: 10.1016/S0303-7207(99)00115-X

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 PPARα, PPARβ (NUC-1) and LXRβ (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-κB transcription factor binding sites. In addition to their effects on transcription, these LXRβ 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.