Inhibition of cholesteryl ester transfer protein activity in hamsters alters HDL lipid composition.
We investigated the role of cholesteryl ester transfer protein (CETP) in hamsters by using a monoclonal antibody (MAb) that inhibited hamster CETP activity. MAbs were prepared against partially purified human CETP and screened for inhibiton of 3H-cholesteryl oleate (CE) transfer from LDL to HDL in the presence of human plasma bottom fraction (d > 1.21 g/ml). Antibody 1C4 inhibited CE transfer activity in both human plasma bottom fraction (IC50 = approximately 4 micrograms/ml) and in whole plasma from male Golden Syrian hamsters (IC50 = approximately 30 micrograms/ml). Purified MAb 1C4 was injected into chow- and cholesterol-fed hamsters, and blood was collected for analysis of plasma CETP activity and HDL lipid composition. Plasma CETP activity was inhibited by 70%-80% at all and HDL lipid composition. Plasma CETP activity was inhibited by 70%-80% at all times up to 24 h following injection of 500 micrograms MAb 1C4 (approximately 3.7 mg/kg). The amount of antibody required for 50% inhibition at 24 h post-injection was 200 micrograms (approximately 1.5 mg/kg). Inhibition of hamster CETP activity in vivo increased hamster HDL cholesterol by 33% (P < 0.0001), increased HDL-CE by 31% (P < 0.0001) and decreased HDL-triglyceride by 42% (P < 0.0001) (n = 36) as determined following isolation of HDL by ultracentrifugation. An increase in HDL cholesterol and a redistribution of cholesterol to a larger HDL particle were also observed following fast protein liquid chromatography (FPLC) gel filtration of plasma lipoproteins.(ABSTRACT TRUNCATED AT 250 WORDS)
Gaynor
B J
BJ
Department of Cardiovascular and Metabolic Diseases, Pfizer, Inc., Groton, CT 06340.
Sand
T
T
Clark
R W
RW
Aiello
R J
RJ
Bamberger
M J
MJ
Moberly
J B
JB
D000818:Animals; D000911:Antibodies, Monoclonal; D001161:Arteriosclerosis / Q000097:blood; D002352:Carrier Proteins / Q000502:physiology*; D053480:Cholesterol Ester Transfer Proteins; D008076:Cholesterol, HDL / Q000097:blood* / Q000737:chemistry; D008078:Cholesterol, LDL / Q000097:blood / Q000737:chemistry; D015243:Cholesterol, VLDL / Q000097:blood / Q000737:chemistry; D006224:Cricetinae; D006023:Glycoproteins; D008297:Male; D008647:Mesocricetus; D010316:Particle Size; D002787:Sterol Esterase / Q000502:physiology*
D000911:Antibodies, Monoclonal; C506642:CETP protein, human; D002352:Carrier Proteins; D053480:Cholesterol Ester Transfer Proteins; D008076:Cholesterol, HDL; D008078:Cholesterol, LDL; D015243:Cholesterol, VLDL; D006023:Glycoproteins; D002787:Sterol Esterase