Background— High-density lipoprotein (HDL) helps to protect against atherosclerosis, not only by enhancing reverse cholesterol transport but also due to its anti-oxidative and anti-inflammatory properties.Although statins potently lower low-density lipoprotein cholesterol (LDL-C), they only have limited ability to raise HDL-C.We recently developed new apo A-I-directed therapies (HDL therapy) using apo A-I discs and Fukuoka apo A-1 mimetic peptide (FAMP, without phospholipids) which consists of 24 amino acids as a modified apoA-i consensus sequence.The aim of the present study is to learn about the effect of FAMP on in vivo macrophage RCT and the underlying mechanisms.Method and Results— Cholesteryl ester transfer protein (CETP) Tg male mice as a model of human were divided into the FAMP and control groups, and injected 50mg/kg/day FAMP or PBS intraperitoneally for 5 days after prefeeding with a 0.5% choresterol diet.After administration, FAMP group decreased HDL cholesterol by 29.9%, and serum from the FAMP group had increased ability to promote ATP-binding cassette transporter A1 (ABCA1) mediated cholesterol effiux by 31.5% from bone marrow macrophages ex vivo.Furthermore, both group of mice were injected intraperitoneally with 3H-cholesterol-labeled and cholesterol-loaded macrophages and monitored for the appearance of 3H-tracer in plasma, and feces.The amount of 3H-tracer excreted into feces over 48 hours in the FAMP group was 42.3% higher that in the control group.Finally, 3H-CEs-HDL was injected intravenously into both groups and blood was taken after HDL injection, and the count of 3H-cholesterol was analyzed.In the FAMP group, plasma 3H-CEsHDL decreased much more rapidly than control group, and FAMP treatment markedly increased fraction catabolic rate by 65.6%.Conclusion— We have demonstrated that administration of new agent FAMP promoted ABCA1 dependent effiux ex vivo, HDL turnover in vivo, and macrophage RCT in vivo on CETP Tg mice despite of the reduced plasma HDL level.These data suggest that administration of FAMP might have tremendous atheroprotective potential and might be new target of treatment for cardiovascular disease.