Identifier

etd-04292010-185535

Degree

Master of Science (MS)

Department

Biological Sciences

Document Type

Thesis

Abstract

Atherosclerosis is the leading cause of mortality in developed countries accounting for 50% of all deaths. Atherosclerosis develops when macrophages in the artery wall accumulate large amounts of cholesterol via uptake of oxidized low density lipoproteins (LDL), causing a negative effect on cholesterol metabolism. Thus, the development of atherosclerosis can be inhibited by increasing cholesterol efflux, which can be achieved by activating ATP binding cassette (ABC) transporters in macrophages. In particular, ABCA1 mediates reverse cholesterol transport to the liver via high density lipoproteins (HDL) and therefore is an attractive molecular target for raising HDL levels and protecting against atherosclerosis. ABCA1 gene expression is known to be regulated by various transcription factors, such as liver X receptor (LXR). LXRs are transcription factors that are activated via binding of ligands, which are oxysterols. Activated LXRs bind to promoter regions at specific sequences known as LXR response elements (LXRE) and regulate genes for cholesterol metabolism and transport, as well as for lipogenesis. Synthetic LXR ligands might be useful for treatment of atherosclerosis if they did not induce lipogenesis, which can lead to an accumulation of cholesterol via activation of steroid response element binding protein (SREBP)-1c in the liver. To develop selective treatments for atherosclerosis, we need to understand mechanisms of selective gene regulation. LXRs occur as two isotypes, LXRα (NR1H3) and LXRβ (NR1H2). Both isotypes regulate genes encoding proteins involved in cholesterol metabolism and transport, as well as in lipogenesis. However, knock-out studies have shown that LXRβ activation results in more effective gene activation in the periphery, such as in macrophages, which can promote cholesterol efflux. The mechanism of this LXR isotype-selectivity is poorly understood. In this document, we will show how protein-protein interactions affect LXRα and LXRβ function and explore the mechanism of nuclear export of LXRα and LXRβ.

Date

2010

Document Availability at the Time of Submission

Release the entire work immediately for access worldwide.

Committee Chair

Donze, David

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