Molecular mechanisms of ABCG1-mediated cholesterol export from macrophages in atherosclerosis

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Copyright: Hsieh, Victar
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Abstract
ABCG1 is a recently discovered ATP-cassette binding transporter that is strongly expressed in cholesterol-loaded macrophages and mediates export of cholesterol from cells to HDL. The thesis reports studies of the factors that control the expression of ABCG1 in vitro and in vivo. It examines the distribution of ABCG1 in the cell and provides direct quantitation of the proportion of ABCG1 that is localised to the plasma membrane in human macrophages. The expression of ABCG1 is associated with increased cell membrane lipid order, without affecting the overall cholesterol and phospholipid compositions in the cell membrane. It is demonstrated that ABCG1 expression is subject to post-translational regulation in human macrophages, where cell cholesterol loading prolongs the half life of ABCG1 protein by preventing ubiquitination and protein degradation mediated by the proteasomal pathway. In human vascular subjects, plasma cholesterol levels were strongly correlated with ABCG1 protein in autologous monocyte-derived macrophages, while only a moderate correlation was observed with ABCG1 mRNA, again highlighting the role of post-translational regulation in expression of the cholesterol transporter. The expression of ABCG1 in macrophages also correlated strongly with glycaemic control in diabetic subjects, suggesting a potentially beneficial effect of good glycaemic control in type II diabetes. Finally, this study demonstrated concordant ABCG1 and ABCA1 protein expression in human atherosclerotic plaque, where macrophages are the cell type which contributes to the majority of ABCG1 in atherosclerotic plaque. We demonstrated for the first time that type II diabetes is associated with decreased abundance of ABCG1 and ABCA1 protein levels in human atherosclerosis. Further investigation into its impact on atherosclerosis progression and plaque stability may provide insight into how this observation affects clinical outcomes in diabetic subjects.
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Hsieh, Victar
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Publication Year
2011
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Thesis
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PhD Doctorate
UNSW Faculty
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