Inhibition of cholesteryl ester transfer protein in normocholesterolemic and hypercholesterolemic hamsters: effects on HDL subspecies, quantity, and apolipoprotein distribution.
The effects of cholesteryl ester transfer protein (CETP) inhibition on the serum lipoprotein profile in both normocholesterolemic and hypercholesterolemic hamsters has been determined following subcutaneous injection of 12.5 mg/kg of the CETP neutralizing monoclonal antibody, TP2. Inhibition of CETP activity was greater than 60% and resulted in a 30-40% increase in high density lipoprotein (HDL) in both normal and hypercholesterolemic animals. These HDL effects were observed 1 day post-injection, were maximal by 4 days, and returned to control values by 14 days. Inhibition of CETP activity resulted in a decrease in both low density lipoprotein (LDL) and very low density lipoprotein (VLDL) cholesterol concomitant with HDL increase, and in hypercholesterolemic animals resulted in increased total serum cholesterol. In addition to the quantitative differences in LDL and HDL, there were significant increases in the size of the HDL, a shift to smaller LDL particles, and changes in apolipoprotein (apo) composition as evaluated by FPLC and Western blot analysis. Large apoA-I-poor and apoE-containing HDL became prevalent in hypercholesterolemic hamsters after CETP inhibition. In addition, the size of the CETP-containing HDL particles increased with inhibition of transfer activity. While these effects were apparent in normocholesterolemic animals, the changes in apolipoprotein distribution and HDL subspecies as detected on native gels were more significant in the hypercholesterolemic animals. The changes in the HDL profile and apolipoprotein distribution after CETP inhibition in hamsters were similar to those reported in CETP-deficient Japanese subjects, suggesting the utility of the hypercholesterolemic hamster as an in vivo model for the understanding of the lipoprotein changes associated with CETP inhibition.
Evans
G F
GF
Division of Cardiovascular Research, Lilly Research Labs, Lilly Corporate Center, Indianapolis, IN 46285.
Bensch
W R
WR
Apelgren
L D
LD
Bailey
D
D
Kauffman
R F
RF
Bumol
T F
TF
Zuckerman
S H
SH
D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D001053:Apolipoproteins / Q000097:blood*; D002352:Carrier Proteins / Q000037:antagonists & inhibitors* / Q000276:immunology; D002784:Cholesterol / Q000097:blood; D053480:Cholesterol Ester Transfer Proteins; D002788:Cholesterol Esters / Q000097:blood; D008076:Cholesterol, HDL / Q000097:blood; D008078:Cholesterol, LDL / Q000097:blood; D015243:Cholesterol, VLDL / Q000097:blood; D006224:Cricetinae; D004195:Disease Models, Animal; D006023:Glycoproteins; D006801:Humans; D006937:Hypercholesterolemia / Q000097:blood*; D008075:Lipoproteins, HDL / Q000097:blood* / Q000145:classification; D008297:Male; D008647:Mesocricetus; D009500:Neutralization Tests
D000911:Antibodies, Monoclonal; D001053:Apolipoproteins; C506642:CETP protein, human; D002352:Carrier Proteins; D053480:Cholesterol Ester Transfer Proteins; D002788:Cholesterol Esters; D008076:Cholesterol, HDL; D008078:Cholesterol, LDL; D015243:Cholesterol, VLDL; D006023:Glycoproteins; D008075:Lipoproteins, HDL; D002784:Cholesterol