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      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.

      Arteriosclerosis, Thrombosis, and Vascular Biology
      1-Alkyl-2-acetylglycerophosphocholine Esterase, blood, metabolism, Animals, Apolipoproteins E, chemistry, Aryldialkylphosphatase, Carrier Proteins, antagonists & inhibitors, physiology, Cholesterol Ester Transfer Proteins, Cholesterol, HDL, Electrophoresis, Capillary, methods, Glycoproteins, Lipoproteins, HDL, Lysophosphatidylcholines, Rabbits, Sulfhydryl Compounds, pharmacology

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          Abstract

          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. 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. 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.

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