Therapeutic strategy for atherosclerosis targeting for CETP

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Background: CETP plays an important role in the reverse cholesterol transport. Inhibition of CETP activity by a CETP inhibitor, JTT-705, increases serum apo A-l levels and inhibits atherosclerosis. To clarify the mechanism by which CETP inhibition increases HDL levels, we examined the effects of JTT-705 on the in vivo kinetics properties of apo A-l in cholesterol-fed rabbits. Methods: Japanese White rabbits were randomly selected to be fed with (a) a normal rabbit chow, LRC-4 (n=10), (b) a diet containing 0.2% cholesterol (n=9), or (c) admixture of (b) and 0.75% JTT-705 (n=7) for 7 mo. CETP activities and serum levels of lipoproteins were measured. In vivo apo A-l kinetics was performed by injecting radioiodinated apo A-l at the end of the study. Results: JTT-705 inhibited 38.5% of the CETP activity in cholesterol-fed rabbits. Cholesterol-feeding decreased SR [8.3 ± 1.1 vs. 10.1 ± 1.8 mg/Kg/day] and serum levels of apo A-l and increased FCR [0.61 ± 0.07 vs. 0.52 ± 0.09 /day] compared with normal chow-feeding. JTT-705 normalized the reduced SR [11.2 ± 2.9 mg/Kg/day] and serum levels of apo A-l and the increased FCR [0.50 ± 0.06 /day] in cholesterol-fed rabbits. Conclusion: Inhibition of CETP activity favorably affects the lipoprotein metabolism in cholesterol-fed rabbits, suggesting that CETP inhibition may be a therapeutic approach for atherosclerosis.