The study investigates the role of liver X receptor (LXR) in controlling lipogenesis, the process of fatty acid biosynthesis. The authors identified two synthetic, nonsteroidal LXR-selective agonists, T0314407 and T0901317, which showed potent activation of LXRα. Oral administration of T0901317 to mice and hamsters increased plasma triglyceride and phospholipid levels, indicating an increase in lipogenesis. Further studies in cell culture and animal models revealed that these increases were mediated through the induction of the sterol regulatory element-binding protein 1 (SREBP-1) lipogenic program. The effects were LXRα-dependent, as demonstrated by the lack of response in LXRα/β−/− mice. The results suggest that LXR agonists can be used to identify key factors linking lipogenesis to triglyceride synthesis and that selective LXRα antagonists may be useful therapeutics for hypertriglyceridemia and cardiovascular disease.The study investigates the role of liver X receptor (LXR) in controlling lipogenesis, the process of fatty acid biosynthesis. The authors identified two synthetic, nonsteroidal LXR-selective agonists, T0314407 and T0901317, which showed potent activation of LXRα. Oral administration of T0901317 to mice and hamsters increased plasma triglyceride and phospholipid levels, indicating an increase in lipogenesis. Further studies in cell culture and animal models revealed that these increases were mediated through the induction of the sterol regulatory element-binding protein 1 (SREBP-1) lipogenic program. The effects were LXRα-dependent, as demonstrated by the lack of response in LXRα/β−/− mice. The results suggest that LXR agonists can be used to identify key factors linking lipogenesis to triglyceride synthesis and that selective LXRα antagonists may be useful therapeutics for hypertriglyceridemia and cardiovascular disease.