Non-redundant roles for LXR alpha and LXR beta in atherosclerosis susceptibility in low density lipoprotein receptor knockout mice

The liver X receptors LXR alpha and LXR beta play critical roles in maintaining lipid homeostasis by functioning as transcription factors that regulate genetic networks controlling the transport, catabolism, and excretion of cholesterol. The studies described in this report examine the individual anti-atherogenic activity of LXR alpha and LXR beta and determine the ability of each subtype to mediate the biological response to LXR agonists. Utilizing individual knockouts of LXR alpha and LXR beta in the Ldlr(-/-) background, we demonstrate that LXR alpha has a dominant role in limiting atherosclerosis in vivo. Functional studies in macrophages indicate that LXR alpha is required for a robust response to LXR ligands, whereas LXR beta functions more strongly as a repressor. Furthermore, selective knockout of LXR alpha in hematopoietic cells and rescue experiments indicate that the anti-atherogenic activity of this LXR subtype is not restricted to macrophages. These studies indicate that LXR alpha plays a selective role in limiting atherosclerosis in response to hyperlipidemia.-Bischoff, E. D., C. L. Daige, M. Petrowski, H. Dedman, J. Pattison, J. Juliano, A. C. Li, and I. G. Schulman. Non-redundant roles for LXR alpha and LXR beta in atherosclerosis susceptibility in low density lipoprotein receptor knockout mice. J. Lipid Res. 2010. 51: 900-906.