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.
Zhang
Bo
B
Department of Cardiology, Fukuoka University School of Medicine, 7-45-1 Nanakuma Jonan-ku, Fukuoka 814-0180, Japan. bozhang@fukuoka-u.ac.jp
Fan
Ping
P
Shimoji
Eiso
E
Xu
Huali
H
Takeuchi
Kazuma
K
Bian
Cheng
C
Saku
Keijiro
K
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