Inhibition of cholesteryl ester transfer protein activity by JTT-705 increases apolipoprotein E-containing high-density lipoprotein and favorably affects the function and enzyme composition of high-density lipoprotein in rabbits.
BACKGROUND
Inhibition of cholesteryl ester transfer protein (CETP) is an efficient way to increase high-density lipoprotein (HDL) levels in humans. We investigated the effects of the inhibition of CETP activity by a CETP inhibitor, JTT-705, on the function and composition of HDL particles.


RESULTS
Japanese white rabbits were fed either normal rabbit chow LRC-4 (n=10) or a food admixture of LRC-4 and 0.75% JTT-705 (n=10) for 7 months. JTT-705 significantly inhibited CETP activities, increased HDL cholesterol (HDL-C) levels and the ratio of HDL2-C/HDL3-C, and decreased the fractional esterification rate of cholesterol in HDL, indicating preferentially increased large HDL particles. Treatment with JTT-705 increased all of the 3 charge-based HDL subfractions as determined by capillary isotachophoresis: fast-migrating, intermediate-migrating, and slow-migrating HDL. The percentage of slow HDL, ie, apolipoprotein E (apoE)-containing HDL and levels of apoE in HDL fraction, was also increased. JTT-705 treatment increased serum paraoxonase activity and HDL-associated platelet-activating factor acetylhydrolase activity, but decreased the plasma lysophosphatidylcholine concentration.


CONCLUSIONS
Inhibition of CETP activity by JTT-705 not only increased the quantity of HDL, including HDL-C levels and charge-based HDL subfractions, but also favorably affected the size distribution of HDL subpopulations and the apolipoprotein and enzyme composition of HDL in rabbits.
Department of Cardiology, Fukuoka University School of Medicine, 7-45-1 Nanakuma Jonan-ku, Fukuoka 814-0180, Japan. bozhang@fukuoka-u.ac.jp
Bo
B
Zhang
Ping
P
Fan
Eiso
E
Shimoji
Huali
H
Xu
Kazuma
K
Takeuchi
Cheng
C
Bian
Keijiro
K
Saku
D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase / Q000097:blood / Q000378:metabolism*; D000577:Amides; D000818:Animals; D001057:Apolipoproteins E / Q000097:blood / Q000737:chemistry* / Q000378:metabolism*; D043303:Aryldialkylphosphatase / Q000097:blood / Q000378:metabolism*; D002352:Carrier Proteins / Q000037:antagonists & inhibitors* / Q000502:physiology*; D053480:Cholesterol Ester Transfer Proteins; D008076:Cholesterol, HDL / Q000097:blood; D019075:Electrophoresis, Capillary / Q000379:methods; D004952:Esters; D006023:Glycoproteins / Q000037:antagonists & inhibitors* / Q000502:physiology*; D008075:Lipoproteins, HDL / Q000097:blood / Q000737:chemistry* / Q000378:metabolism*; D008244:Lysophosphatidylcholines / Q000097:blood; D011817:Rabbits; D013438:Sulfhydryl Compounds / Q000494:pharmacology*
D000577:Amides; D001057:Apolipoproteins E; D002352:Carrier Proteins; D053480:Cholesterol Ester Transfer Proteins; D008076:Cholesterol, HDL; D004952:Esters; D006023:Glycoproteins; D008075:Lipoproteins, HDL; D008244:Lysophosphatidylcholines; D013438:Sulfhydryl Compounds; C411602:dalcetrapib; D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase; D043303:Aryldialkylphosphatase