Dalcetrapib
JTT-705 raises HDL cholesterol in rabbits by speeding up apolipoprotein A-I synthesis, not by slowing its breakdown (Atherosclerosis 2004)
Original title: Inhibition of cholesteryl ester transfer protein increases serum apolipoprotein (apo) A-I levels by increasing the synthesis of apo A-I in rabbits
Researchers investigated how the CETP inhibitor JTT-705 affects the in vivo kinetics of apolipoprotein A-I (apoA-I) and its gene expression in the liver and intestine. Japanese white rabbits were fed normal chow or chow admixed with 0.75% JTT-705 for 7 months, with apoA-I kinetics measured using radiolabeled apoA-I injection and hepatic and intestinal apoA-I mRNA quantified by RT-PCR. JTT-705 significantly inhibited CETP activity and raised serum HDL cholesterol, HDL2 cholesterol, HDL phospholipid, and apoA-I, while lowering HDL triglyceride. The synthetic rate of apoA-I was higher in treated rabbits than controls (13.7 plus or minus 2.6 versus 9.5 plus or minus 1.3 mg per kg per day, p < 0.05), while the fractional catabolic rate was unchanged, and JTT-705 raised apoA-I mRNA in the liver but not the intestine, indicating that CETP inhibition raises HDL levels by boosting hepatic apoA-I synthesis rather than by slowing its clearance.
Original abstract
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.
Conclusion: 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.
dalcetrapibHDL biologymechanisms
Summary written by cetpinhibition.org from the published abstract; figures as published. Page updated 18 August 2026. Methods.