Role of nuclear receptors in macrophage development and function

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dc.contributor.advisorNagy, László
dc.contributor.authorSzántó, Attila
dc.contributor.departmentDE -- Orvos- és Egészségtudományi Centrum -- Általános Orvostudományi Kar -- Biokémiai és Molekuláris Biológiai Intézethu
dc.contributor.departmentElméleti orvostudományok doktori iskolahu
dc.date.accessioned2007-06-21T07:45:06Z
dc.date.available2007-06-21T07:45:06Z
dc.date.defended2004-12-10
dc.date.issued2004
dc.description.abstractNuclear 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.en
dc.description.degreeEgyetemi doktori Ph.D. értekezés ; Department of Biochemistry and Molecular Biology, Research Center for Molecualr Medicine, Medical and Health Sciences Center, University of Debrecen, 2004hu
dc.description.degreePhDhu_HU
dc.format.extent90 pen
dc.format.extent420946 bytes
dc.format.extent302880 bytes
dc.format.extent1197637 bytes
dc.format.mimetypeapplication/pdf
dc.format.mimetypeapplication/pdf
dc.format.mimetypeapplication/pdf
dc.identifier.urihttp://hdl.handle.net/2437/2434
dc.languageenghu
dc.language.isohuen
dc.language.isoenen
dc.rightsA kéziratos PhD munkák csak a szerzői jogok maradéktalan tiszteletben tartásával használhatókhu
dc.titleRole of nuclear receptors in macrophage development and functionen
dc.title.subtitlethesis for the degree of Doctor of Philosophy (Ph.D.)en
dc.title.translatedMagreceptorok szerepe a makrofágok fejlődésében és funkciójábanen
dc.typePhD, doktori értekezéshu
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