Despite the significant advances in treatment of coronary disease due to use of statins, atherosclerosis still causes significant morbidity. Clinical data suggest that enhancing reverse cholesterol transport (RCT) could further improve clinical outcomes. Agonists of the liver X receptor (LXR) that mediate macrophage cholesterol efflux are on the horizon. In contrast, peroxisome proliferator-activated receptor α (PPARα) agonists that also increase RCT are already in the clinic, but their effectiveness has been somewhat limited. In this issue, Mukherjee et al. describe two new PPARα agonists, with more than 100-fold higher affinity than the clinically used fibrates. Their results in mouse and hamster show increased cholesterol high-density lipoprotein and decreased low-density lipoprotein and triglycerides, respectively, in plasma. When combined with an LXR agonist, the new PPARα agonists also exhibited potent synergy in cholesterol excretion, suggesting that these are potential treatments for heart disease.
See article at J Pharmacol Exp Ther 2008, 327:716–726.
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