Liver X receptor (LXR) agonists have the potential to treat
atherosclerosis based on their ability to enhance reverse
cholesterol transport. However, their side effects, such as induction of liver lipogenesis and triglyceridemia, may limit their
pharmaceutical development. In contrast to the nonsteroidal LXR agonist N-(2,2,2-trifluoroethyl)-N-[4-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]phenyl]-
benzenesulfonamide (
T0901317), 3alpha, 6alpha, 24-trihydroxy-24, 24-di(trifluoromethyl)-5beta-cholane (ATI-829), a novel potent synthetic steroidal LXR agonist, was a poor inducer of
sterol regulatory element-binding protein 1c expression in
hepatoma HepG2 cells, whereas both compounds increased ABCA1 expression in macrophage THP-1 cells. In male
low-density lipoprotein receptor-deficient mice,
ATI-829 selectively activated LXR target gene expression in mouse intestines and macrophages but not in the liver. A significant increase in liver
triglyceride and plasma triglyceriderich small
very low-density lipoprotein (VLDL) was observed in
T0901317 but not ATI-829-treated mice. Compared with vehicle-treated mice,
atherosclerosis development was significantly inhibited in the innominate artery
after treatment with either compound. However, in the aortic root, inhibition of
atherosclerosis was only observed in the right (right coronary artery-associated sinus) but not the left coronary-related sinus (left coronary artery-associated sinus; LC) of mice treated with either compound. Lesions in the innominate artery were less complex
after treatment with either compound and contained mostly macrophage foam cells. In contrast, LC lesions were more complex and had a large
collagen-positive fibrous cap and less macrophage foam cell area
after treatment with either compound. The T0901317-induced
hypertriglyceridemia was accompanied by an increase in small
triglyceride-rich VLDL that may influence LXR agonist-mediated antiatherosclerotic effects at certain vascular sites.
ATI-829, by selectively activating LXR in certain tissues without inducing
hypertriglyceridemia, is a good candidate for
drug development.