Use this URL to cite or link to this record in EThOS: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.583587
Title: Studies on the regulation of apolipoprotein E gene expression in macrophages
Author: Greenow, Kirsty
Awarding Body: Cardiff University
Current Institution: Cardiff University
Date of Award: 2005
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Abstract:
It was decided to investigate the regulation of apoE by the LXR subfamily of nuclear receptors. LXRs have atheroprotective properties due to their ability to upregulate the expression of genes involved in the reverse cholesterol transport process. ApoE is a direct target of these ligand-mediated transcription factors and a clearer understanding of the LXR-mediated transcription of apoE would aid the development of potential therapeutic agents for atherosclerosis. Therefore, the involvement of signal transduction pathways in the LXR-mediated regulation of apoE in macrophages was investigated. Through the use of commercially available inhibitors, we firstly identified a novel role for the JNK/SAPK MAPK, P13K and CK2 pathways in the LXR-mediated induction of apoE mRNA protein and secretion in human THP-1 macrophages. This inhibition of apoE induction was also shown to occur in human primary monocyte-derived macrophages and further investigations demonstrated the potential role of these cell signalling pathways in the LXR-mediated regulation of ABCA1, ABCG1 and LXR?. It was also found, for the first time, that treatment of THP-1 macrophages with the oxysterol LXR ligand, 22(R)-hydroxycholesterol, induced JNK phosphorylation and kinase activity, and the subsequent phosphorylation of the c-jun transcription factor. Treatment of THP-1 macrophages with the LXR ligand also resulted in the phosphorylation and activation of Akt, a downstream component of PI3K signalling. In addition CK2 activity was found to be increased in THP-1 macrophages treated with 22(R)-hydroxycholesterol. In conclusion, the studies presented in this thesis demonstrated, for the first time, an important role for the JNK/SAPK MAPK, P13K and CK2 pathways in the activation of macrophage apoE gene expression by the LXR subfamily of nuclear receptors. A potential role for these cell signalling pathways was also implicated in the LXR-mediated regulation of ABCA1, ABCG1 and LXR?.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.583587  DOI: Not available
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