Cell-based cotransfection assays have demonstrated that SR9238 is a synthetic inverse agonist for LXR, with IC50 values of 214 nM for LXRα and 43 nM for LXRβ. SR9238 also effectively inhibits the transcription of a luciferase reporter gene driven by the Fasn promoter. It has been found that SR9238 induces an increase in the interaction of CoRNR box peptides derived from NCoR (NCoR ID1 and NCoR ID2) with LXRα and LXRβ, while decreasing the interaction with coactivator NR box peptides derived from TRAP220. The recruitment of CoRNR box peptides induced by SR9238 is dose-dependent for both LXRα and LXRβ. Treatment of HepG2 cells with SR9238 results in a significant reduction in the expression of Fasn and Srebp1c mRNA[1].
SR9238 动物研究
Animal study
In animal studies, approximately 6 μM of SR9238 was detected in the liver 2 hours post-injection, while the compound was not detected in the plasma. SR9238 was also found in the intestines following intraperitoneal injection or oral administration. Treatment with SR9238 significantly reduced lipid content in the livers of mice. Compared to control mice, those treated with SR9238 showed a marked decrease in the expression of TNF-α and Il1b (approximately 80% and >95%, respectively). Mice treated with SR9238 exhibited notably lower F4/80 staining intensity compared to control DIO mice, consistent with the beneficial effects of SR9238 on NASH. Throughout the experiment, SR9238 treatment did not alter body weight or the percentage of body fat composition relative to vehicle-treated animals. SR9238 treatment was able to inhibit diet-induced hepatic steatosis, liver inflammation, and hepatocellular damage[1].
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