Abstract 584: A Synthetic Farnesoid X Receptor Agonist Protects Against Diet-Induced Dyslipidemia
The nuclear hormone receptor farnesoid X Receptor (FXR) plays a critical role in the regulation of bile acid synthesis and triglyceride (TG) and cholesterol homeostasis. The synthetic ligand WAY-362450 (FXR-450) has been shown to be a potent FXR agonist using both in vitro reporter assays and monitoring cell based gene expression. FXR-450 stimulated a luciferase reporter driven by human FXR with an EC50 of 16 nM and also activated known FXR target genes in primary human and mouse hepatocytes. Here we demonstrate that FXR-450 has potent lipid-lowering activity in several animal dyslipidemia models. In LDLR KO mice consuming a Western diet or in the diabetic db/db or KKAy mouse models, FXR-450 dose dependently decreased serum TG and serum and hepatic cholesterol levels after 7 days of oral dosing. The reduction of total cholesterol levels by FXR-450 was due to reductions in the VLDL, LDL and HDL fractions. The mechanism of cholesterol lowering in the various mouse strains appears to be due to a combination of reduced cholesterol absorption and increased billiary cholesterol excretion via ABCG5 and ABCG8 regulation. Similar effects on serum TG and VLDL, LDL and HDL cholesterol levels were obtained with FXR-450 treatment in male hamsters, which have a bile acid physiology more closely resembling humans. In a fructose fed rat model, FXR-450 decreased TG and VLDL cholesterol levels. However, in contrast to mice and hamsters, FXR-450 significantly increased HDL cholesterol levels in the rat. Although FXR has been suggested to modulate apoAI expression, FXR-450 did not repress apoAI gene expression in LDLR KO mice, human apoAI transgenic mice, or rats. The basis for the species-specific effects of FXR-450 on HDL cholesterol levels remains to be determined. These studies demonstrate a consistent ability of FXR-450 to lower both serum TG and cholesterol levels in multiple settings and suggest that synthetic FXR agonists may have clinical utility in the treatment of dyslipidemia.