Inhibition of cholesteryl ester transfer protein increases serum apolipoprotein (apo) A-I levels by increasing the synthesis of apo A-I in rabbits.
BACKGROUND
Inhibition of cholesteryl ester transfer protein (CETP) is an effective way to increase HDL levels in animals and humans. The effects of a CETP inhibitor, JTT-705, on the in vivo kinetics of apolipoprotein (apo) A-I and apo A-I gene expression in the liver and intestine were investigated.


METHODS
Japanese White rabbits were randomly fed normal rabbit chow LRC-4 (n=10, control) or a food admixture of LRC-4 and 0.75% JTT-705 (n=10, treated) for 7 months. An in vivo kinetics study of apo A-I was performed by injecting rabbit 125I-apo A-I, and apo A-I mRNA levels were quantified by RT-PCR.


RESULTS
JTT-705 significantly inhibited CETP activities, increased serum levels of HDL-cholesterol (C), HDL2-C, HDL-phospholipid, and apo A-I, and decreased HDL-triglyceride levels. The synthetic rate of apo A-I was higher in the treated rabbits than in control rabbits (13.7 +/- 2.6 versus 9.5 +/- 1.3 mg/kg per day, P < 0.05), while the fractional catabolic rate was similar in the two groups. JTT-705 increased apo A-I mRNA levels in the liver without affecting those in the intestine.


CONCLUSIONS
Inhibition of CETP activity by JTT-705 increases HDL levels by increasing the synthesis of apo A-I, suggesting that it could be a promising therapeutic approach for atherosclerosis.
Shimoji
Eiso
E
Department of Cardiology, Fukuoka University School of Medicine, 7-45-1 Nanakuma Jonan-ku, Fukuoka 814-0180, Japan.
Zhang
Bo
B
Fan
Ping
P
Saku
Keijiro
K
D000577:Amides; D000818:Animals; D016632:Apolipoprotein A-I / Q000096:biosynthesis* / Q000097:blood* / Q000235:genetics; D002352:Carrier Proteins / Q000037:antagonists & inhibitors*; D053480:Cholesterol Ester Transfer Proteins; D008076:Cholesterol, HDL / Q000097:blood; D004952:Esters; D015870:Gene Expression; D006023:Glycoproteins; D008075:Lipoproteins, HDL / Q000097:blood; D053439:Lipoproteins, HDL2; D008297:Male; D011817:Rabbits; D013438:Sulfhydryl Compounds / Q000494:pharmacology; D014280:Triglycerides / Q000097:blood
D000577:Amides; D016632:Apolipoprotein A-I; D002352:Carrier Proteins; D053480:Cholesterol Ester Transfer Proteins; D008076:Cholesterol, HDL; D004952:Esters; D006023:Glycoproteins; C034396:HDL-triglyceride; D008075:Lipoproteins, HDL; D053439:Lipoproteins, HDL2; D013438:Sulfhydryl Compounds; D014280:Triglycerides; C411602:dalcetrapib