Accumulation of Foam Cells in Liver X Receptor-Deficient Mice

Background—The nature of some of the target genes for liver X receptors (LXRs)-&agr; and -&bgr;, such as sterol regulatory element binding protein-1 and ATP-binding cassette transporter proteins, suggests a pivotal role of these nuclear receptors in the regulation of fatty acid and cholesterol homeostasis. The present study aimed to elucidate the physiological relevance of both LXRs with regard to lipid metabolism and macrophage cholesterol efflux. Methods and Results—Mice depleted for LXR&agr;, LXR&bgr;, or both were fed low-fat rodent chow for 18 months before investigations. The combined deficiency of LXR&agr; and LXR&bgr; was linked to impaired triglyceride metabolism, increased LDL and reduced HDL cholesterol levels, and cholesterol accumulation in macrophages (foam cells) of the spleen, lung, and arterial wall. Conclusions—Our data demonstrate the physiological importance of both LXRs in lipid metabolism and strongly indicate that both LXRs have a protective role against the development of atherosclerosis.