Is There a Need for Cholesteryl Ester Transfer Protein Inhibition?
For the past twenty years, LDL cholesterol (LDL-C) has been the primary target of therapeutic approaches to prevent coronary heart disease (CHD). Reduction of plasma LDL-C has been successfully achieved by lifestyle changes, treatment by HMG CoA reductase inhibitors, the statins, and most recently, with cholesterol absorption inhibition via ezetimibe.1 However, the identification of HDL cholesterol (HDL-C) as an independent risk factor for CHD, with the recognition that higher plasma HDL-C is associated with a decreased incidence of coronary events,2 has prompted research for new therapeutic agents that raise HDL-C. The hope is that raising HDL-C will signal an increase in the movement of cholesterol from the periphery back to the liver (the so-called reverse cholesterol transport or RCT pathway) and protection from CHD will follow. In the February issue of Atherosclerosis Thrombosis and Vascular Biology, Barter and colleagues3 provide an interesting review focusing on the plasma cholesteryl ester transfer protein (CETP) as a novel target for raising HDL-C thereby reducing CHD. Their suggestion is that the time may be right for clinical trials to test this concept. Should we support this position?
See February, page 160
CETP is a hydrophobic plasma glycoprotein, mainly synthesized in the liver, possessing the unique ability to facilitate the transfer of cholesteryl ester (CE). HDLs are lipoprotein particles formed in the plasma compartment.4 Apolipoprotein (apo)A-I interacts on cell surfaces with the ABCA1 transporter and becomes lipidated with phospholipid and cholesterol. Subsequently, the enzyme LCAT interacts with these newly formed lipoproteins and catalyzes the formation of cholesteryl esters from the phospholipids and cholesterol of the nascent HDL. Cholesteryl esters are highly hydrophobic lipids that form the core of lipoprotein particles and can only leave plasma with the intact HDL particle, per se, or through facilitated, protein-mediated transfer from HDL to other lipoproteins that are then removed. The rates of clearance of the apoB-containing acceptor lipoproteins are normally much faster than for HDL, so that the degree to which CE is transferred via CETP into these lipoproteins could have a significant role in RCT. To the extent that CETP is present in sufficient amounts, this transfer should result in efficient clearance of CE from plasma, and the action of CETP would appear to be an anti-atherogenic factor that prevents the accumulation of cholesterol in tissues such as the artery. If the clearance from plasma of acceptor lipoproteins slows and the CE from HDL actually accumulate in the apoB-containing lipoproteins, then the action of CETP would be pro-atherogenic.
Whether CETP is a pro- or anti-atherogenic protein has been debated for years, and many studies have been done, motivated by the need for understanding the physiological and pathophysiological role of CETP in lipoprotein metabolism. The initial observations were that animals naturally lacking CETP activity are resistant to the development of atherosclerosis while those expressing CETP are sensitive to diet-induced atherosclerosis. One of the first direct demonstrations that CETP may act as a promoter of CHD was done in the early 1990s in nonhuman primates.5 Cynomolgus monkeys were fed cholesterol-enriched diets, and the extent of coronary artery atherosclerosis was positively correlated to plasma CETP mass and inversely correlated to HDL cholesterol concentrations. Other studies done in animals that express CETP, such as those on rabbit aortic atherosclerosis as reviewed by Barter et al,3 also support the potential pro-atherogenic role of CETP. Additional observations indicate that humans bearing mutations in the CETP gene which result in CETP deficiency may be at a lower risk of developing CHD. Together, these observations all suggest that CETP could be a promoter of atherosclerosis.
Mice are now the most commonly used animal model of atherosclerosis. This animal naturally lacks CETP, and the expression of the CETP gene in mice has resulted both in promotion and prevention of aortic atherosclerosis (for review see Barter et al3). In C57/BL6, apoE knockout, APOBEC-1 knockout, and LDL-receptor knockout mice, transgenic expression of CETP resulted in a redistribution of CE from HDL into apoB-containing lipoproteins and an increased development of atherosclerosis was reported. However, in other mouse models such as apoE knockout/human apoA-I transgenic, human apoC-III transgenic, human LCAT transgenic, and hypertriglyceridemic mice, expression of the CETP gene has been reported to protect against atherosclerosis.
Taken together, the studies in animals have revealed the complexity of CETP function in lipoprotein metabolism and showed that in conditions where CE-rich apoB-containing lipoproteins accumulate, CETP may exhibit both pro- and anti-atherogenic effects. However in most cases, it has not been made clear whether modifications in CETP associated with atherosclerosis were due to the parallel change in HDL-C. The studies in nonhuman primates suggested that the positive relationship between CETP and coronary artery atherosclerosis may have been mediated more strongly through effects of CETP to increase LDL cholesterol than to reduce HDL cholesterol.5 Interestingly, data from the administration of a new synthetic CETP inhibitor (JTT-705) in rabbits seems similar to the observation in nonhuman primates. When rabbits challenged with 0.2% dietary cholesterol were treated with JTT-705 for six months, a reduction in aortic arch lesion area was observed.6 In these animals, JTT-705 treatment increased HDL-C by 90% and decreased non–HDL-C by 40% to 50%. However, in rabbits that developed a more severe hypercholesterolemia, JTT-705 failed to reduce the extent of the atherosclerotic lesions.7 In this latter model, a doubling of HDL-C was reported, but it was associated with less decrease (−25%) in non–HDL-C. Furthermore, the extent of the atherosclerosis was correlated with non–HDL-C and not with HDL-C. The message that CETP mediates CHD primarily through its effects on HDL is not firmly established by the animal studies.
Family, clinically based, and population studies have also been done to establish whether CETP is a pro-atherogenic protein in humans (for review see Barter et al3). Mutations and/or polymorphisms in the CETP gene have been extensively investigated to correlate CETP deficiency to a high HDL-C level and to a lower CHD prevalence. The outcome of these studies confirms the lesson from the animal studies: the role of CETP in lipoprotein metabolism and in the development of atherosclerosis is very complex and may reflect the interaction of this protein with several factors. High levels of HDL-C are very likely associated with a reduced risk of CHD. However, this association seems to be independent of the presence of CETP deficiency. For example, Barter et al3 report in their review that the recent analysis of the 7 years prospective data from the Honolulu Heart Study showed no relationship between heterozygous mutation of CETP and CHD or stroke.
The relationship between CETP gene polymorphism and CHD seems dependent on sex and lifestyle habits including alcohol intake.3 In addition, very little is known about the possible roles played by the CETP inhibitors naturally present in plasma, including apoF and apoC-I.8–10⇓⇓ Higher CETP activity may contribute to a more atherogenic lipoprotein phenotype through increasing the amounts of CE in apoB-containing lipoproteins. However, at the same time, CETP deficiency leads to the formation of larger and CE-rich HDL also enriched in apoE, and these particles may be poor cholesterol acceptors.11 But based on available evidence, it is not possible to ascertain whether possible protective effects of CETP deficiency are attributable to the increase in HDL-C, to the decrease in LDL-C, or both.
Clarification of the primary effect of CETP inhibition on CHD would not be only of great scientific value but also of strategic interest. The attractiveness of powerful HDL-C–elevating drugs is great (presuming this increase would also signal increased RCT) and remains a frontier in lipid research. The interest in another LDL-C–lowering drug would be lower due to the outstanding effectiveness shown by the statins particularly when combined with the new drug ezetimibe.1 Interestingly, a 4-week treatment with the synthetic CETP inhibitor JTT-705, at a dose of 900 mg/d, in healthy subjects led to a greater increase (34%) in HDL-C than to a decrease in LDL-C (−7%).12 Thus, the goal for increasing HDL-C and reducing CHD might be met through an approach to inhibit CETP. In our opinion, even if the data available from human and animal studies do not always suggest that CETP is pro-atherogenic, there are no data suggesting that pharmacologic inhibition of CETP activity in humans would be harmful. Thus, CETP inhibitors might be a powerful tool for increasing HDL-C, decreasing LDL-C, and reducing the development of atherosclerosis. Perhaps the recommendation made by Barter et al3 for defined clinical trials on CETP inhibition would serve to provide answers to this important question.
- ↵Barter PJ, Brewer HB Jr, Chapman MJ, Hennekens CH, Rader DJ, Tall AR. Cholesteryl ester transfer protein: a novel target for raising HDL and inhibiting atherosclerosis. Arterioscler Thromb Vasc Biol. 2003; 23: 160–167.
- ↵Quinet E, Tall A, Ramakrishnan R, Rudel L. Plasma lipid transfer protein as a determinant of the atherogenicity of monkey plasma lipoproteins. J Clin Invest. 1991; 87: 1559–1566.
- ↵Wang X, Driscoll DM, Morton RE. Molecular cloning and expression of lipid transfer inhibitor protein reveals its identity with apolipoprotein F. J Biol Chem. 1999; 274: 1814–1820.
- ↵Gautier T, Masson D, Jong MC, Duverneuil L, Le Guern N, Deckert V, Pais de Barros JP, Dumont L, Bataille A, Zak Z, Jiang XC, Tall AR, Havekes LM, Lagrost L. Apolipoprotein CI deficiency markedly augments plasma lipoprotein changes mediated by human cholesteryl ester transfer protein (CETP) in CETP transgenic/ApoCI-knocked out mice. J Biol Chem. 2002; 277: 31354–31363.
- ↵Gautier T, Masson D, de Barros JP, Athias A, Gambert P, Aunis D, Metz-Boutigue MH, Lagrost L. Human apolipoprotein C-I accounts for the ability of plasma high density lipoproteins to inhibit the cholesteryl ester transfer protein activity. J Biol Chem. 2000; 275: 37504–37509.
- ↵Ishigami M, Yamashita S, Sakai N, Arai T, Hirano K, Hiraoka H, Kameda-Takemura K, Matsuzawa Y. Large and cholesteryl ester-rich high-density lipoproteins in cholesteryl ester transfer protein (CETP) deficiency can not protect macrophages from cholesterol accumulation induced by acetylated low-density lipoproteins. J Biochem (Tokyo). 1994; 116: 257–262.
- ↵de Grooth GJ, Kuivenhoven JA, Stalenhoef AF, de Graaf J, Zwinderman AH, Posma JL, van Tol A, Kastelein JJ. Efficacy and safety of a novel cholesteryl ester transfer protein inhibitor, JTT-705, in humans: a randomized phase II dose-response study. Circulation. 2002; 105: 2159–2165.