Nagy, LászlóSzántó, Attila2007-06-212007-06-212004http://hdl.handle.net/2437/2434Nuclear receptors are ligand-activated transcription factors that regulate many aspects of metazoan life. In vivo, a biologically active, functional nuclear receptor requires obviously the protein of the transcription factor, an endogenous ligand that activates it and appropriate conditions in the cell. This latter mainly depends on the presence of elements of co-activator complexes and the permissive, epigenetic status of the regulated DNA. Nuclear receptors have been shown to be important in regulating lipid metabolism in myeloid cells and were also implicated in differentiation processes of the myeloid lineage. Peroxisome Proliferator Activated Receptor γ (PPARγ) appears to be a key component of lipid uptake by inducing the scavenger receptor CD36 that mediates oxidized low-density lipoprotein (oxLDL) uptake to macrophages. Retinoic Acid Receptor (RAR) on the other hand was also shown to play important roles in myeloid cell differentiation. • We present evidence for a crosstalk between these two nuclear receptor pathways in myeloid cells and show that expression level of PPARγ increases with the degree of monocyte/macrophage commitment. Activation of PPARγ leads to the increased expression of maturation markers (e.g. CD14, CD36). Interestingly, retinoid treatment potentiates PPARγ ability to induce transcription of its target genes. Cholesterol uptake and efflux are key metabolic processes associated with macrophage physiology and atherosclerosis. PPARγ and Liver X Receptor α (LXRα) have been linked to the regulation of these processes. • 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. Induction of the enzyme results in an increased level of 27-hydroxycholesterol that activates LXR and LXR-regulated processes, which leads to an alternative means of cholesterol efflux. 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 a key integrator of RAR-PPARγ-LXR signaling. • We also analyzed the activation state of macrophages and found that PPARγ is dominantly expressed in alternatively activated macrophages and induces target genes’ expression mostly in this specialized cell type.90 p420946 bytes302880 bytes1197637 bytesapplication/pdfapplication/pdfapplication/pdfhuA kéziratos PhD munkák csak a szerzői jogok maradéktalan tiszteletben tartásával használhatókPhD, doktori értekezés