Submitted to: Journal of Lipid Research
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 11/7/2007
Publication Date: 3/20/2008
Citation: Millar, J.S., Brousseau, M.E., Diffenderfer, M.R., Barrett, H.R., Welty, F.K., Cohn, J.S., Wilson, A., Wolfe, M.L., Martsupha, C., Schaefer, P.M., Digenio, A.G., Mancuso, J.P., Dolnikowski, G.G., Schaefer, E.J., Rader, D.J. 2008. Effects of the cholesteryl ester transfer protein inhibitor torcetrapib on VLDL apolipoprotein E metabolism. Journal of Lipid Research. 49:543-549. Interpretive Summary: The major cholesterol carrying particles in the bloodstream are known as low density lipoproteins or LDL. High levels of LDL cholesterol (> 160 mg/dl) have been associated with an increased risk of heart disease, a leading cause of death and disability in our society. Another cholesterol carrying particle in the bloodstream is known as high density lipoprotein cholesterol. Low levels of high density lipoprotein (HDL) cholesterol (< 40 mg/dl in men and < 50 mg/dl in women) have also been associated with an increased risk of heart disease. LDL is known to deposit cholesterol in tissues, while HDL is known to remove it for return to the liver and excretion from the body. Diets low in animal fat and cholesterol as well as statin drugs lower LDL cholesterol and reduce heart disease risk. However for many people with heart disease especially those with low HDL, these steps are not enough, and they may go on to have another heart attack. For this reason people have tried to develop ways to raise HDL. One way to do this is to prevent the transfer of cholesterol with a fatty acid attached to it (known as cholesteryl ester) from being transferred from HDL to other lipoproteins that cause heart disease such as very low density lipoproteins (VLDL) or LDL. Such medicines have been developed and they are known as cholesteryl ester transfer protein (CETP) inhibitors and markedly increase HDL cholesterol. We studied the effects of the CETP inhibitor Torcetrapib on the metabolism of one the proteins in VLDL known as apolipoprotein (apo) E. This protein is important for the liver uptake of chylomicrons and their remnants (cholesterol and triglyceride-rich particles made in the intestine) and VLDL. In 19 subjects with low HDL we studied the metabolism of VLDL apoE using stable isotope (non-radioactive) methods in humans. The use of torcetrapib was associated with lower levels of VLDL cholesterol and apoE, and enhanced breakdown of the VLDL apoB and apoE. These data indicate that if cholesteryl ester is prevented from getting onto VLDL from HDL, it will enhance the breakdown of the VLDL, and decrease heart disease risk. It is known that lowering elevated blood cholesterol ( > 240 mg/dl) and elevated low density lipoprotein (LDL) cholesterol ( > 160 mg/dl) with diet and statin medications can reduce the risk of heart disease. However there are many people who receive such treatment who go on to develop heart disease or to have a recurrent event. Many of these people have a low high density lipoprotrein (HDL) cholesterol level ( < 40 mg/dl). Therefore it is important to develop strategies to treat low HDL cholesterol. One way to do this is to prevent the transfer of a form of cholesterol known cholesteryl ester (cholesterol with a fatty acid attached to it) by inhibiting cholesteryl ester transfer protein or CETP. We tested the CETP inhibitor torcetrapib and found that it decreased the amount of cholesteryl ester, and the proteins apolipoprotein (apo) B and apo E in triglyceride-rich lipoproteins known as very low density lipoproteins (VLDL). By using stable isotope methods in humans we have documented that this effect is due to enhanced breakdown of the particle VLDL in the bloodstream. Therefore CETP inhibition can lower heart disease risk by preventing the transfer of cholesteryl ester from HDL to triglyceride-rich lipoproteins or VLDL. Other CETP inhibitors that do not lower blood pressure, blood potassium, or have other off target effects, appear to be more promising at this time, and are being tested in large clinical studies.
Technical Abstract: Our purpose was to evaluate associations of single nucleotide polymorphisms (SNPs) at the low density lipoprotein (LDL) receptor (LDLRC44857T, minor allele frequency (MAF) 0.26, and A44964G, MAF 0.25, both in the untranslated region) and HMG-CoA reductase (HMGCRi18 T >G, MAF 0.019) gene loci with baseline lipid values, statin-induced LDL-cholesterol (C) lowering response, and incident coronary heart disease (CHD) and cardiovascular disease (CVD) on trial. Our population consisted of 5804 elderly men and women with vascular disease or one or more vascular disease risk factors, who were randomly allocated to pravastatin or placebo. Other risk factors and apolipoprotein (apo) E phenotype were controlled for in the analysis. Despite a prior report, no relationships with the HMGCR SNP were noted. For the LDLR SNPs C44857T and A44964G we noted significant associations of the rare alleles with baseline LDL-C and triglyceride levels, a modest association of the C44857T with LDL-C lowering to pravastatin in men, and significant associations with incident CHD and CVD of both SNPs, especially in men on pravastatin. Our data indicate that genetic variation at the LDLR locus can affect baseline lipids, response to pravastatin, and CVD risk in subjects placed on statin treatment.