Reverse cholesterol transport and future pharmacological approaches to the treatment of atherosclerosis.
The apparent protective effect of high density lipoprotein cholesterol (HDL) with respect to coronary heart disease (CHD) is generally thought to reside in its ability to transport cholesterol from peripheral cells to the liver for excretion from the body. Knozon as reverse cholesterol transport (RCT), this process involves many key steps and lipoprotein interconversions, and there is no consensus as to which step is most suitable for possible drug intervention. The membrane proteins, scavenger receptor class B, type 1 (SR-B1) and the ATP-binding cassette 1 (ABC1), have been strongly implicated as being important in cholesterol efflux; the former as a bona fide receptor for HDL and the latter as a lipid transporter. Lecithin:cholesterol acyltransferase (LCAT) then esterifies the effluxed cholesterol to form cholesteryl esters (Step 2), which are then transferred to apoB-containing lipoproteins by cholesteryl ester transfer protein (CETP, Step 3). Despite the complexities and uncertainties, drugs should be developed which impact all of the above steps, and short-term endpoints need to be defined for a cautious, systematic approach to clinical evaluation.
Krause
B R
BR
Department of Cardiovascular Therapeutics, Pfizer Global Research and Development, Ann Arbor, MI 48105, USA. brian.krause@pfizer.com
Auerbach
B J
BJ
D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism; D000818:Animals; D016632:Apolipoprotein A-I / Q000096:biosynthesis* / Q000235:genetics; D001693:Biological Transport, Active; D018955:CD36 Antigens / Q000235:genetics / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D002784:Cholesterol / Q000737:chemistry / Q000378:metabolism*; D053480:Cholesterol Ester Transfer Proteins; D002788:Cholesterol Esters / Q000378:metabolism; D008076:Cholesterol, HDL / Q000096:biosynthesis* / Q000097:blood; D003324:Coronary Artery Disease / Q000378:metabolism / Q000517:prevention & control*; D004195:Disease Models, Animal; D018390:Gene Targeting; D006023:Glycoproteins; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008565:Membrane Proteins; D051379:Mice; D018345:Mice, Knockout; D007862:Phosphatidylcholine-Sterol O-Acyltransferase / Q000235:genetics / Q000378:metabolism; D011971:Receptors, Immunologic; D018110:Receptors, Lipoprotein; D051116:Receptors, Scavenger; D051122:Scavenger Receptors, Class B; D014280:Triglycerides / Q000378:metabolism; D015854:Up-Regulation
D018528:ATP-Binding Cassette Transporters; D016632:Apolipoprotein A-I; D018955:CD36 Antigens; C506642:CETP protein, human; D002352:Carrier Proteins; D053480:Cholesterol Ester Transfer Proteins; D002788:Cholesterol Esters; D008076:Cholesterol, HDL; D006023:Glycoproteins; D008565:Membrane Proteins; D011971:Receptors, Immunologic; D018110:Receptors, Lipoprotein; D051116:Receptors, Scavenger; C495124:SCARB1 protein, human; C454739:Scarb1 protein, mouse; D051122:Scavenger Receptors, Class B; D014280:Triglycerides; D002784:Cholesterol; D007862:Phosphatidylcholine-Sterol O-Acyltransferase