The role of liver X receptors in atherosclerosis

The interaction of oxidized low-density lipoprotein (oxLDL) with cells of the artery wall is central to the pathogenesis of atherosclerosis. Members of the nuclear receptor superfamily are recognized to be important mediators of the effects of lipids on cellular gene expression. Work presented in this thesis has helped to define a role for the nuclear receptors LXRalpha and LXRbeta in the macrophage response to oxidized lipid loading and has provided evidence for a direct link between the LXR signaling pathway and the development of atherosclerosis.;The first part of this thesis is focused on the characterization of the lipid metabolic pathways controlled by LXRs. Studies in macrophages implicate LXRs in the regulation of reverse cholesterol transport. LXRs promotes cholesterol removal from the cell through the coordinate regulation of genes involved in the cholesterol efflux pathway including the cholesterol/phospholipid transporter ATP-binding cassette 1 (ABCA1) and apolipoprotein E (apoE). Enforced expression of LXRalpha in macrophages leads to the promotion of LXR target genes and to the stimulation of cholesterol efflux. In human macrophages, this pathway is amplified through an autoregulatory loop in which LXRs control expression of the LXRalpha promoter. In addition, this work has clarified a role for LXR in the control of hepatic lipogenesis. The identification of the fatty acid synthase (FAS) gene as an LXR target using microarray technology led to the discovery of a novel regulatory arrangement on the FAS promoter. LXRs were shown to regulate fatty acid synthase (FAS) gene expression through direct interaction with the FAS promoter as well as through activation of SREBP-1c expression.;The second part of the thesis is directed at testing the influence of LXR signaling pathways on the development of atherosclerosis in vivo. Bone marrow transplantations were performed to selectively eliminate LXR activity in macrophages and other hematopoetic cells. Genetic ablation of LXRs in hematopoetic cells dramatically increased lesion development in two different mouse models of cardiovascular disease. This observation strongly supports the hypothesis that the LXR pathway serves to protect against macrophage lipid overload in vivo. The final results presented in this thesis suggest that LXR may be an excellent therapeutic target for the prevention of atherosclerotic disease. Administration of a potent synthetic LXR ligand to two different atherosclerotic mouse models decreased lesion formation approximately 50%. This effect correlated with stimulation of ABCA1 and ABCG1 expression in the aortas of the treated mice.