Reduction of atherosclerosis in apolipoprotein E knockout mice by activation of the retinoid X receptor

A common feature of many metabolic pathways is their control by retinoid X receptor (RXR) heterodimers. Dysregulation of such metabolic pathways can l ead to the development of atherosclerosis, a disease influenced by both sys temic and local factors. Here we analyzed the effects of activation of RXR and some of its heterodimers in apolipoprotein E -/- mice, a well establish ed animal model of atherosclerosis. An RXR agonist drastically reduced the development of atherosclerosis. In addition, a ligand for the peroxisome pr oliferator-activated receptor (PPAR)gamma and a dual agonist of both PPAR a lpha and PPAR gamma had moderate inhibitory effects. Both RXR and liver X r eceptor (LXR) agonists induced ATP-binding cassette protein 1 (ABC-1) expre ssion and stimulated ABC-l-mediated cholesterol efflux from macrophages fro m wild-type, but not from LXR alpha and beta double -/-, mice. Hence, activ ation of ABC-1-mediated cholesterol efflux by the RXR/LXR heterodimer might contribute to the beneficial effects of rexinoids on atherosclerosis and w arrant further evaluation of RXR/LXR agonists in prevention and treatment o f atherosclerosis.