Cholesteryl ester transfer protein: a novel target for raising HDL and inhibiting atherosclerosis.
Cholesteryl ester transfer protein (CETP) promotes the transfer of cholesteryl esters from antiatherogenic HDLs to proatherogenic apolipoprotein B (apoB)-containing lipoproteins, including VLDLs, VLDL remnants, IDLs, and LDLs. A deficiency of CETP is associated with increased HDL levels and decreased LDL levels, a profile that is typically antiatherogenic. Studies in rabbits, a species with naturally high levels of CETP, support the therapeutic potential of CETP inhibition as an approach to retarding atherogenesis. Studies in mice, a species that lacks CETP activity, have provided mixed results. Human subjects with heterozygous CETP deficiency and an HDL cholesterol level >60 mg/dL have a reduced risk of coronary heart disease. Evidence that atherosclerosis may be increased in CETP-deficient subjects whose HDL levels are not increased is difficult to interpret and may reflect confounding or bias. Small-molecule inhibitors of CETP have now been tested in human subjects and shown to increase the concentration of HDL cholesterol while decreasing that of LDL cholesterol and apoB. Thus, it seems important and timely to test the hypothesis in randomized trials of humans that pharmacological inhibition of CETP retards the development of atherosclerosis.
Barter
Philip J
PJ
Hanson Institute and the Department of Cardiology, Royal Adelaide Hospital, Adelaide, Australia. p.barter@hri.org.au
Brewer
H Bryan
HB
Chapman
M John
MJ
Hennekens
Charles H
CH
Rader
Daniel J
DJ
Tall
Alan R
AR
D000577:Amides; D000818:Animals; D001053:Apolipoproteins / Q000502:physiology; D001161:Arteriosclerosis / Q000097:blood / Q000209:etiology / Q000517:prevention & control*; D002352:Carrier Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000502:physiology; D053480:Cholesterol Ester Transfer Proteins; D002788:Cholesterol Esters / Q000097:blood / Q000378:metabolism; D008076:Cholesterol, HDL / Q000097:blood*; D015986:Confounding Factors, Epidemiologic; D004952:Esters; D006023:Glycoproteins; D006801:Humans; D008052:Lipid Metabolism, Inborn Errors / Q000097:blood / Q000150:complications / Q000235:genetics; D008074:Lipoproteins / Q000097:blood / Q000378:metabolism; D013438:Sulfhydryl Compounds / Q000627:therapeutic use
D000577:Amides; D001053:Apolipoproteins; C506642:CETP protein, human; D002352:Carrier Proteins; D053480:Cholesterol Ester Transfer Proteins; D002788:Cholesterol Esters; D008076:Cholesterol, HDL; D004952:Esters; D006023:Glycoproteins; D008074:Lipoproteins; D013438:Sulfhydryl Compounds; C036321:apolipoprotein F; C411602:dalcetrapib