Transcriptional regulation of human CYP27 integrates retinoid, peroxisome proliferator-activated receptor, and liver X receptor signaling in macrophages
| Autor: | Szilvia Benko, Laszlo Nagy, Sándor Molnár, Ralph Rühl, Sebastiano Calandra, Attila Szanto, R. Garuti, Ulf Diczfalusy, Hanna Larsson, Balint L. Balint, László Csiba, Istvan Szatmari, Ibolya Fürtös |
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| Jazyk: | angličtina |
| Rok vydání: | 2004 |
| Předmět: |
PPARgamma
Transcription Genetic Arteriosclerosis Receptors Retinoic Acid Receptors Cytoplasmic and Nuclear Biológiai tudományok Biology Retinoid X receptor Ligands Gene Expression Regulation Enzymologic Liver X receptor beta Mice Retinoids Természettudományok Animals Humans Liver X receptor Promoter Regions Genetic Molecular Biology CYP27 gene Cells Cultured Liver X Receptors Transcriptional Regulation Retinoid X receptor alpha Macrophages Retinoic Acid Receptor alpha human macrophage liver X receptor alpha (LXRalpha) Liver X receptor alpha Cell Biology Cholesterol loading Retinoid X receptor gamma Orphan Nuclear Receptors Hydroxycholesterols Cell biology DNA-Binding Proteins Retinoid X Receptors Biochemistry Steroid Hydroxylases Cholestanetriol 26-Monooxygenase lipids (amino acids peptides and proteins) Institut für Ernährungswissenschaft Peroxisome proliferator-activated receptor alpha Retinoid X receptor beta Signal Transduction Transcription Factors |
| Popis: | Cholesterol uptake and efflux are key metabolic processes associated with macrophage physiology and atherosclerosis. Peroxisome proliferator-activated receptor gamma (PPARgamma) and liver X receptor alpha (LXRalpha) have been linked to the regulation of these processes. It remains to be identified how activation of these receptors is connected and regulated by endogenous lipid molecules. We identified CYP27, a p450 enzyme, as a link between retinoid, PPARgamma, and LXR signaling. We show that the human CYP27 gene is under coupled regulation by retinoids and ligands of PPARs via a PPAR-retinoic acid receptor response element in its promoter. Induction of the enzyme's expression results in an increased level of 27-hydroxycholesterol and upregulation of LXR-mediated processes. Upregulated CYP27 activity also leads to LXR-independent elimination of CYP27 metabolites as an alternative means of cholesterol efflux. Moreover, human macrophage-rich atherosclerotic lesions have an increased level of retinoid-, PPARgamma-, and LXR-regulated gene expression and also enhanced CYP27 levels. Our findings suggest that nuclear receptor-regulated CYP27 expression is likely to be a key integrator of retinoic acid receptor-PPARgamma-LXR signaling, relying on natural ligands and contributing to lipid metabolism in macrophages. |
| Databáze: | OpenAIRE |
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