Abstract 13576: Highly Selective LXRbeta Selective Agonist Prevents Progression of Atherosclerotic Lesion without Elevation of Triglyceride

Abstract

Introduction: It is well known that Liver X Receptors (LXRs) are highly linked with regulation of lipid metabolism. Several LXR agonists were challenged for the prevention or treatment of atherosclerosis in animal models, but the unexpected elevation of triglyceride level was observed presumably due to LXRalpha agonistic action. In this study, we evaluated anti-atherosclerotic effects of K-20950, a novel and highly selective LXRbeta agonist.

Methods and Results: The EC50 values of K-20950 for LXRalpha and LXRbeta were 60 nM and 2.5 nM, respectively, which is 24 times highly selective for LXRbeta. In vitro examinations, K-20950 increased the expression of ABCA1 in J774A.1, RAW264.7, and THP-1, at EC50 of 2 nM, 8 nM, and 0.7 nM, respectively. Additionally, K-20950 increased cholesterol efflux via ApoA1 with dose dependent manner, and sub-maximal effect at concentration of 1 microM were 19.3±0.8% and 19.8±0.4% for J774A.1 and THP-1, respectively. In vivo experiment using LDL receptor knockout mice, twelve-weeks oral administration of K-20950 (1 mg/kg) significantly prevented the progression of aortic lipid deposition area by 56.5%, without affecting triglyceride levels in the liver (128±53 vs. 92±62 mg/g tissue, n=12) compared with control group. GW3965 (10 mg/kg), a non-selective LXR agonist, also prevented the progression of aortic lipid deposition, but it increased triglyceride level markedly in the liver. Oral administration of K-20950 also significantly prevented the aortic lipid content and increased the excretion of macrophage-derived cholesterol into feces compared with control (0.7±0.2 vs. 3.2±1.5%, n=4∼5) in high cholesterol diet-fed hamsters.

Conclusions: These results suggest that selective LXRbeta agonist can augment the reverse cholesterol transport system without affecting a triglyceride level, and provides a novel approach for the prevention or treatment of atherosclerosis.