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Title: Liver-X-receptor-mediated expression of key genes in macrophages implicated in the control of cholesterol homeostasis and atherosclerosis
Author: Huwait, Etimad A.
Awarding Body: Cardiff University
Current Institution: Cardiff University
Date of Award: 2008
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Abstract:
Atherosclerosis is a leading cause of morbidity and mortality in the western world. The deposition of lipoprotein cholesterol in the arterial wall is a critical early step in the pathogenesis of atherosclerosis. These atherogenic lipoproteins are then taken up by macrophages to transform into lipid-loaded foam cells. ATP-binding cassette transporter-Ai (ABCAi) is a membrane-bound protein that mediates efflux of cholesterol from cells, such as macrophages. Tangier disease, which arises due to mutations in the ABCAi gene, is associated with foam cells in a number of tissues and premature atherosclerosis. Proteins in HDL, such as apolipoprotein E (apoE), act as acceptors of cholesterol released from macrophages via the action of ABCAi, and take it to the liver where it can be excreted through the bile system. Increasing the expression of both ABCAi and apoE is therefore considered as a potential therapeutic approach for the prevention or treatment of atherosclerosis. Liver-X-receptors (LXRs) are members of a subfamily of nuclear receptors that are potent activators of ABCAi and apoE expression. Agonists of LXRs inhibit macrophage foam cell formation in vitro and atherosclerosis in mouse models of the disease. The signalling pathways through which LXR agonists induce the expression of ABCAi and apoE expression in macrophages are not known. The major aim of the studies presented in this thesis was to investigate such signalling pathways using the human macrophage THP-1 cell line as a model system with key findings confirmed in primary cultures. Both natural LXR agonists, such as combinations of 22-(R)-hydroxycholesterol (22-(R)-HC) and 9-cis-retinoic acid (9CRA), and synthetic ligands induced the expression of ABCAi and apoE. Such an induction of ABCAi and apoE expression was attenuated by treatment of the cells with pharmacological inhibitors of c-Jun-N-terminal kinase/stress- activated kinase (JNK/SAPK) and phosphoinositide-3-kinase (PI3K) pathways. The action of 22-(R)-HC and 9CRA was associated with activation of JNK/SAPK, its upstream component SEK1/MKK4 and its down-stream target c-Jun along with the key target for PI3K, protein kinase B (PKB). The role of these pathways was confirmed further by analysing the action of expression of dominant negative forms of key proteins on the activation of ABCAi promoter. In addition, small interfering RNA-mediated knockdown of JNK/SAPK was found to attenuate the induction of apoE expression. The action of these pathways culminated at the level of activator protein-1, a transcription factor that contains c-Jun, and whose binding sites are present in the regulatory regions of both the apoE and ABCAi genes. Finally, a potential cross-talk between the JNK/SAPK and PI3K pathways was identified in which protein kinase C played an important role. In conclusion, the studies presented in this thesis demonstrated, for the first time, an important role for a pathway involving PKB, PKC and JNK/SAPK cascade in the activation of ABCAi and apoE expression by LXR agonists, which has implications to macrophage foam cell formation and atherosclerosis.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.584316  DOI: Not available
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