LXR (Liver X Receptor) plays a crucial role in lipid metabolism, particularly in cholesterol and fatty acid biosynthesis. This study identifies T0314407 and T0901317 as nonsteroidal LXR agonists that activate the expression of genes involved in lipogenesis, leading to increased plasma triglyceride and phospholipid levels in mice and hamsters. The mechanism involves LXR-mediated induction of SREBP-1, a key regulator of fatty acid and lipid metabolism. The results show that LXR agonists significantly enhance lipogenesis and triglyceride synthesis, with effects dependent on LXR activity. In LXRα/β double knockout mice, the lipid response was diminished, confirming the essential role of LXRs in these processes. The study also highlights the direct interaction of LXR agonists with LXRα, and their ability to activate LXR-dependent gene expression. These findings suggest that LXR agonists can be used to modulate lipid metabolism, offering potential therapeutic applications for hypertriglyceridemia and related metabolic disorders. The study provides insights into the transcriptional regulation of lipid metabolism by LXRs, emphasizing their role in controlling fatty acid biosynthesis and triglyceride synthesis. The results support the use of LXR agonists as a therapeutic strategy for lipid-related diseases.LXR (Liver X Receptor) plays a crucial role in lipid metabolism, particularly in cholesterol and fatty acid biosynthesis. This study identifies T0314407 and T0901317 as nonsteroidal LXR agonists that activate the expression of genes involved in lipogenesis, leading to increased plasma triglyceride and phospholipid levels in mice and hamsters. The mechanism involves LXR-mediated induction of SREBP-1, a key regulator of fatty acid and lipid metabolism. The results show that LXR agonists significantly enhance lipogenesis and triglyceride synthesis, with effects dependent on LXR activity. In LXRα/β double knockout mice, the lipid response was diminished, confirming the essential role of LXRs in these processes. The study also highlights the direct interaction of LXR agonists with LXRα, and their ability to activate LXR-dependent gene expression. These findings suggest that LXR agonists can be used to modulate lipid metabolism, offering potential therapeutic applications for hypertriglyceridemia and related metabolic disorders. The study provides insights into the transcriptional regulation of lipid metabolism by LXRs, emphasizing their role in controlling fatty acid biosynthesis and triglyceride synthesis. The results support the use of LXR agonists as a therapeutic strategy for lipid-related diseases.