Abstract 1450: The Novel Thyromimetic KAT-681 Promotes Macrophage Reverse Cholesterol Transport In Vivo And Protects From Atherosclerosis
Background- We describe the characterization of the novel liver-selective thyromimetic KAT-681 (KAT) displaying strong hypolipidemic properties without cardio-toxic effects.
Results- In BALB/c mice, KAT treatment (36 nmol/kg/d) led to a 50 % decrease of plasma cholesterol, accompanied by an 1.6-fold increased fecal excretion of cholesterol and by a 50% decreased intestinal absorption of diet-derived plant sterols (all P<0.001). Hepatic expression of scavenger receptor-BI (SR-BI) was increased 2-fold, when compared to controls (P<0.001). In vivo reverse cholesterol transport (RCT) measurements were performed 48 hours after intraperitoneal injection of cholesterol-loaded, [3H]-labeled J774 macrophages. Compared to controls, KAT-treated mice showed 60% lower [3H]-cholesterol levels in plasma (P<0.001), no changes in hepatic [3H]-cholesterol, and a 3.5-fold increase in fecal [3H]-cholesterol (P<0.001). In New Zealand White (NZW) rabbits fed a high-cholesterol diet, KAT-treatment (36 nmol/kg/d) decreased plasma cholesterol and triglyceride (TG) levels by 60% and by 80%, respectively (both P<0.001). FPLC analysis revealed a marked decrease in both atherogenic very low density lipoprotein (VLDL) and LDL cholesterol, without changes in HDL. Hepatic expression of SR-BI and LDL receptor (LDLr) were increased 2-fold (both P<0.01), without changes in plasma CETP activity. Most importantly, Sudan IV-staining of rabbit aortas revealed a 60% decrease of atherosclerotic lesion area, when compared to controls (P<0.001).
Conclusions- Our data show that KAT-681 protects from atherosclerosis by promoting RCT. We, therefore suggest that liver-specific thyromimetics are likely to represent novel drugs for the prevention and treatment of atherosclerosis in humans.