Inhibition of cholesteryl ester transfer protein increases serum apolipoprotein (apo) A-I levels by increasing the synthesis of apo A-I in rabbits.

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.

• Authors: Eiso Shimoji, Bo Zhang, Ping Fan, Keijiro Saku
• Journal: Atherosclerosis (Atherosclerosis) Vol. 172 Issue 2 Pg. 247-57 (Feb 2004) ISSN: 0021-9150 [Print] Ireland
• PMID: 15019534 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Amides
• Apolipoprotein A-I
• Carrier Proteins
• Cholesterol Ester Transfer Proteins
• Cholesterol, HDL
• Esters
• Glycoproteins
• HDL-triglyceride
• Lipoproteins, HDL
• Lipoproteins, HDL2
• Sulfhydryl Compounds
• Triglycerides
• dalcetrapib

Topics

• Amides
• Animals
• Apolipoprotein A-I (biosynthesis, blood, genetics)
• Carrier Proteins (antagonists & inhibitors)
• Cholesterol Ester Transfer Proteins
• Cholesterol, HDL (blood)
• Esters
• Gene Expression
• Glycoproteins
• Lipoproteins, HDL (blood)
• Lipoproteins, HDL2
• Male
• Rabbits
• Sulfhydryl Compounds (pharmacology)
• Triglycerides (blood)