Received August 8, 2007
Revised September 5, 2007
Accepted after revision October 11, 2007
Cardiovascular Control [210]
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'Cholesterol metabolism and therapeutic molecules
Valentine Charlton-Menys 1
Paul Durrington 1*
1 University of Manchester
* To whom correspondence should be addressed. E-mail: pdurrington{at}manchester.ac.uk.
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Abstract |
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There has been a fascinating interplay between the discovery of some of the key enzymes, receptors and transporters in cholesterol biosynthesis and transfer and the development of drugs for the regulation of cholesterol metabolism.
The discovery of the low density lipoprotein (LDL) receptor lead to the realisation that circulating LDL cholesterol could be decreased when hepatic LDL receptor expression was stimulated by decreasing intrahepatic cholesterol levels. The first of the drugs which operate in this way were the bile acid sequestrating agents, which, by interrupting the enterohepatic circulation of bile acids, deplete the liver of cholesterol used to replenish the pool of bile salts. Ezetimibe, which was developed to block cholesterol absorption from the intestine led to the discovery of the Nieman-Pick C1-Like 1 sterol transporter channel. The statins, which have proved enormously successful in preventing cardiovascular disease, were discovered amongst fungal metabolites which inhibit hydroxyl methyl CoA reductase, the rate limiting enzyme for hepatic cholesterol biosynthesis. Drugs which block enzymes at other stages of the cholesterol biosynthetic pathway, particularly the squalene synthase inhibitors, are entering the clinical phase of their development. Drugs which interfere with hepatic very low density lipoprotein assembly in the liver, such as microsomal triglyceride transfer protein inhibitors and apolipoprotein B mRNA antisense oligonucleotides, are currently undergoing evaluation. Cholesteryl ester transfer protein (CETP) inhibitors, which decrease cholesteryl ester heteroexchange within the circulation, have undergone development to the point of clinical evaluation and this will eventually settle the controversy about whether CETP is pro- or anti-atherogenic.
Corresponding author P.N. Durrington, Cardiovascular Research Group, School of Clinical & Laboratory Sciences, Core Technology Facility (3rd Floor), University of Manchester 46 Grafton Street, Manchester M13 9NT email: pdurrington@manchester.ac.uk
Key Words:
Coronary artery, Metabolism, Molecular biology
