Transcriptional regulation of human CYP27 integrates retinoid, peroxisome proliferator-activated receptor, and liver X receptor signaling in macrophages.
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.
Szanto
Attila
A
Department of Biochemistry and Molecular Biology, Research Center for Molecular Medicine, University of Debrecen, Hungary.
Benko
Szilvia
S
Szatmari
Istvan
I
Balint
Balint L
BL
Furtos
Ibolya
I
Rühl
Ralph
R
Molnar
Sandor
S
Csiba
Laszlo
L
Garuti
Rita
R
Calandra
Sebastiano
S
Larsson
Hanna
H
Diczfalusy
Ulf
U
Nagy
Laszlo
L
D000818:Animals; D001161:Arteriosclerosis / Q000201:enzymology / Q000378:metabolism; D002478:Cells, Cultured; D053493:Cholestanetriol 26-Monooxygenase; D004268:DNA-Binding Proteins; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006801:Humans; D006888:Hydroxycholesterols / Q000378:metabolism; D008024:Ligands; D000071518:Liver X Receptors; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D057093:Orphan Nuclear Receptors; D011401:Promoter Regions, Genetic; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists / Q000378:metabolism*; D018168:Receptors, Retinoic Acid / Q000378:metabolism; D000072482:Retinoic Acid Receptor alpha; D047488:Retinoid X Receptors; D012176:Retinoids / Q000494:pharmacology; D015398:Signal Transduction; D013250:Steroid Hydroxylases / Q000235:genetics*; D014157:Transcription Factors / Q000819:agonists / Q000378:metabolism; D014158:Transcription, Genetic
D004268:DNA-Binding Proteins; D006888:Hydroxycholesterols; D008024:Ligands; D000071518:Liver X Receptors; C000605213:NR1H3 protein, human; C000605214:Nr1h3 protein, mouse; D057093:Orphan Nuclear Receptors; C000607071:RARA protein, human; C000607072:Rara protein, mouse; D018160:Receptors, Cytoplasmic and Nuclear; D018168:Receptors, Retinoic Acid; D000072482:Retinoic Acid Receptor alpha; D047488:Retinoid X Receptors; D012176:Retinoids; D014157:Transcription Factors; C076996:27-hydroxycholesterol; D013250:Steroid Hydroxylases; C506831:CYP27A1 protein, human; D053493:Cholestanetriol 26-Monooxygenase; C506832:Cyp27a1 protein, mouse