Abstract 1451: Effect of Macrophage Specific Over-expression of Liver X Receptor-α on Atherosclerosis in LDL-receptor Deficient Mice
Objective: The nuclear liver X receptor-α (LXR-α) has been implicated in the regulation of intracellular cholesterol homeostasis and atherosclerosis susceptibility by up-regulating proteins involved in reverse cholesterol transport. These studies were based on knockout mouse models of LXR for reduced expression and treatment of mice with LXR agonists for increased expression of LXR. The results led to the hypothesis that increased expression of LXR-α might result in an improvement of cholesterol homeostasis and reduction of atherosclerosis.
Methods and Results: To address this question, we generated mice with macrophage specific over-expression of mouse LXR-α under the control of a chicken lysozyme genomic DNA construct. Macrophages from transgenic mice indeed showed significantly elevated expression levels of LXR-target genes (ABCA1) compared to non-transgenic controls. To assess the effect of the transgene on atherosclerosis susceptibility, mice were crossed onto the LDL-receptor deficient background. Plasma total cholesterol, triglycerides, LDL- and HDL-cholesterol concentrations were not significantly different between transgenic animals and non-transgenic controls. However, lesion area at the brachiocephalic artery (BCA) was significantly reduced (−83%, p=0.02) in male LXR-α transgenic mice. This was associated with a significantly increased cholesterol efflux to acceptor-free media (+24%, p=0.002) and ApoA1 containing media (+20%, p<0.0001) from macrophages of transgenic animals, thus providing a potential mechanism for reduced atherosclerosis.
Conclusions: Our data show for the first time that transgenic overexpression of LXR-α using a macrophage-specific gene construct has anti-atherogenic properties. We conclude that over-expression of LXR-α might be useful as a therapeutic principle for the prevention of atherosclerosis.