The Role of Liver X Receptors in Reverse Cholesterol Transport and Atherosclerosis

Breevoort, Sarah, Pharmacology - Graduate School of Arts and Sciences, University of Virginia
Schulman, Ira, Department of Pharmacology, University of Virginia

Liver X receptors (LXRα and LXRβ) are important regulators of cholesterol and lipid metabolism, and their activation has been shown to inhibit cardiovascular disease and reduce atherosclerosis in animal models. Believed to be integral to their anti-atherogenic effects, LXRs regulate reverse cholesterol transport (RCT), the process by which high density lipoprotein (HDL) particles transport cholesterol from peripheral cells such as lipid-laden macrophages to the liver for catabolism and excretion. LXRs regulate RCT by controlling cholesterol efflux from macrophages to HDL and the excretion, catabolism and absorption of cholesterol in the liver and intestine. Deletion of LXR activity in macrophages increases atherosclerosis; a consequence thought to result from the loss of LXR stimulated RCT. Nevertheless, the relative contribution of LXR activity in the macrophage, liver and intestine to LXR stimulated RCT has not been determined. Utilizing tissue-specific LXR deletions we demonstrate that macrophage LXR activity is neither necessary nor sufficient for LXR agonists to promote RCT. Furthermore, our studies suggest that the ability of macrophages to efflux cholesterol to HDL in vivo is not regulated in a cell autonomous fashion but is primarily determined by the quantity and quality of the HDL particles.
While macrophage LXR is not necessary for LXR agonist stimulated RCT, liver LXRα is required for agonist stimulated fecal cholesterol excretion. Interestingly, when the liver specific LXRα deficient mice are challenged with dietary cholesterol the ability of LXR agonists to increase macrophage efflux in is lost. To investigate if the loss of LXR agonist stimulated RCT increases atherosclerosis, we crossed the liver-specific LXRα deficient mouse into a pro-atherogenic background. Hyperlipidemic liver-specific LXRα knockout animals had a significant reduction in agonist-stimulated macrophage cholesterol efflux and fecal cholesterol excretion, highlighting an important role for hepatic LXRα in regulating RCT and cholesterol metabolism. Deletion of liver LXRα also results in increased atherosclerosis, uncovering an important function for hepatic LXRα activity in limiting cardiovascular disease. Nevertheless, synthetic LXR agonists were still protective against atherosclerosis in the absence of hepatic LXRα. Together our data suggests that LXR agonist-stimulated RCT may not be necessary for the anti-atherogenic activity of LXR agonists; however, LXR expression in the macrophage is required for their protective effects. In addition to promoting cholesterol efflux LXR agonists exert anti-inflammatory effects in macrophages, and this function may in fact underlie their athero-protective activities. Future studies from this work might elucidate the contribution of macrophage LXR anti-inflammatory activity to the cardio-protective effects of LXR agonists. Such findings could provide valuable insight for future therapeutic strategies for the treatment of cardiovascular disease.

PHD (Doctor of Philosophy)
atherosclerosis, transcription factors, liver X receptors, pharmacology
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