Transcriptional regulation of human CYP27 integrates retinoid, peroxisome proliferator-activated receptor, and liver X receptor signaling in macrophages

Attila Szanto, Szilvia Benko, Istvan Szatmari, Balint L. Balint, Ibolya Furtos, Ralph Rühl, Sandor Molnar, Laszlo Csiba, Rita Garuti, Sebastiano Calandra, Hanna Larsson, Ulf Diczfalusy, Laszlo Nagy

Research output: Contribution to journalArticle

Abstract

Cholesterol uptake and efflux are key metabolic processes associated with macrophage physiology and atherosclerosis. Peroxisome proliferator-activated receptor gamma (PPARγ) and liver X receptor alpha (LXRα) 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, PPARγ, 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-, PPARγ-, 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-PPARγ-LXR signaling, relying on natural ligands and contributing to lipid metabolism in macrophages.

Original languageEnglish (US)
Pages (from-to)8154-8166
Number of pages13
JournalMolecular and cellular biology
Volume24
Issue number18
DOIs
StatePublished - Sep 2004

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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    Szanto, A., Benko, S., Szatmari, I., Balint, B. L., Furtos, I., Rühl, R., Molnar, S., Csiba, L., Garuti, R., Calandra, S., Larsson, H., Diczfalusy, U., & Nagy, L. (2004). Transcriptional regulation of human CYP27 integrates retinoid, peroxisome proliferator-activated receptor, and liver X receptor signaling in macrophages. Molecular and cellular biology, 24(18), 8154-8166. https://doi.org/10.1128/MCB.24.18.8154-8166.2004