doi: 10.1161/01.ATV.0000214979.24518.95
© 2006 American Heart Association, Inc.
Editorials |
Cholesteryl Ester Transfer Protein Inhibition
Effect on Reverse Cholesterol Transport?
From the Departments of General Internal Medicine, Endocrinology, and Metabolic Diseases (P.C.N.R., L.M.H.) and Cardiology (L.M.H.), Leiden University Medical Center, and TNO-Quality of Life, Department of Biomedical Research (L.M.H.), Gaubius Laboratory, Leiden, The Netherlands.
Correspondence to Patrick C.N. Rensen, PhD, Leiden University Medical Center, Department of Endocrinology and Metabolic Diseases, C4-R81, Albinusdreef 2, P.O. Box 9600, 2300 RC Leiden, The Netherlands. E-mail P.C.N.Rensen{at}lumc.nl
Statins, inhibitors of the key enzyme in the biosynthesis of cholesterol (ie, 3-hydroxy-3-methylglutaryl [HMG]-coenzyme A [CoA] reductase), are widely used as the prevailing strategy to combat atherosclerosis through reducing LDL cholesterol levels. Large-scale clinical trials have shown that statins markedly reduce coronary events.1,2 A meta-analysis of 22 studies enrolling nearly 70 000 individuals indicated that an effective decrease of LDL cholesterol by 20% to 40% reduces non-fatal myocardial infarction or coronary heart disease mortality by 25%.3 Although of clear clinical benefit, lowering LDL cholesterol alone using statin monotherapy thus does not prevent 75% of all cardiovascular events, which has led to a considerable interest in targeting other lipid-related risk factors.
See page 884
Prospective epidemiological studies have shown a strong inverse correlation between HDL cholesterol levels and cardiovascular disease.4 In fact, a low HDL level, often seen in combination with elevated triglyceride (TG) levels, is the primary lipid abnormality in &50% of men with coronary heart disease.5 Recent studies revealed that high HDL cholesterol levels are indeed protective against plaque progression.6 It has been shown that pharmacological intervention leading to an increase of HDL cholesterol by 1% is associated with a 2% to 3% decrease in cardiovascular risk.7 Although the exact mechanisms through which HDL protects are unclear, HDL has been shown to have antioxidant, antithrombotic, and antiinflammatory properties,8 and to mediate the flux of excess cholesterol from peripheral cells to the liver followed by excretion via the feces in a process referred to as reverse cholesterol transport (RCT).9
Based on these beneficial properties of HDL, pharmacological raising of HDL cholesterol levels is thought to hold promise in the treatment of atherosclerotic cardiovascular disease.10–12 Current therapies with statins, fibrates, and nicotinic acid (niacin), which aim at targeting LDL/VLDL metabolism, appear to raise HDL as an advantageous side effect. Meta-analyses of trials with statins, fibrates, and niacin showed an increase of HDL cholesterol of &5%,13 10%,14 and 16%,14 respectively. Statins increase HDL cholesterol probably in part via reduction of cholesteryl ester transfer protein (CETP)-mediated neutral lipid transfer.15 Fibrates enhance the de novo synthesis of HDL in the liver and small intestine by increasing apoAI synthesis via activation of the nuclear transcription factor peroxisome proliferative activated receptor-
(PPAR),16 and fibrates possibly also decrease CETP activity.17 Niacin increases HDL through a mechanism that is still largely unknown but appears to involve decreased apoAI catabolism.18,19
To date, there exists no therapy that is specifically designed to raise HDL cholesterol levels, but CETP inhibition is making strong headway over the last few years with phase III trials ongoing. CETP is mainly produced by the liver and macrophages and plays an important role in HDL metabolism. In plasma, CETP facilitates the transfer of TG and cholesteryl esters (CE) between apoB-containing lipoproteins and HDL, resulting in the net transfer of CE mass from HDL to apoB-containing lipoproteins.20 By decreasing HDL cholesterol, CETP may thus represent an atherogenic factor. Genetic association studies in humans showed an association of the C-629A promoter variant of CETP with higher CETP levels, lower HDL cholesterol levels, and an increased progression of CAD.21 Likewise, increased CETP activity was associated with increased risk for CAD in subjects with elevated TG.22 Although studies in apoCIII-transgenic mice and LCAT-transgenic mice showed that human CETP expression reduced atherosclerosis,23,24 expression of CETP in mice that are hyperlipidemic because of attenuated hepatic uptake of apoE-containing lipoprotein remnants (ie, apoE-deficient and LDL receptor–deficient mice) increased atherosclerosis.25 Recent studies from our laboratory have shown that human CETP expression in hyperlipidemic APOE*3-Leiden transgenic mice, with a human-like lipoprotein profile, also causes a tremendous increase in atherosclerosis development (Marit Westerterp, Caroline C. van der Hoogt, L.M.H., P.C.N.R., unpublished observations).
Based on these data, CETP inhibition is now widely regarded as a promising novel therapeutic target for raising HDL cholesterol to inhibit atherosclerosis.26 Indeed, initial clinical studies with the first two available CETP inhibitors (ie, JTT-705 and torcetrapib) demonstrated a marked increase in HDL cholesterol levels. JTT-705 (900 mg once daily) increased HDL cholesterol (34%) and decreased LDL-cholesterol (7%).27 Torcetrapib (120 mg once daily) increased HDL cholesterol (46% to 73%), apoAI (16% to 24%), and apoE (47%), as reflected by the accumulation of larger HDL particles, and concomitantly reduced LDL-cholesterol (8% to 21%) and apoB (10% to 12%).28,29 Dosing twice daily raised HDL cholesterol even further (91% to 106%). It is, however, still unknown whether these potent effects of CETP inhibition will be pro- or antiatherogenic. For example, CETP mutations have been described that associate with decreased CETP activity, increased HDL cholesterol, and increased CAD.30 Second, although one hallmark study in cholesterol-fed rabbits did show that JTT-705 decreased atherosclerosis,31 no effect was observed in a subsequent study using more severely hypercholesterolemic rabbits despite a 2.5-fold increase in HDL cholesterol.32
A major concern with the use of CETP inhibitors as a strategy to raise HDL cholesterol levels is the fact that the serum HDL level does not necessarily reflect its functional benefit, eg, with respect to the role of HDL in RCT. On accepting cholesterol from peripheral cells such as macrophages in the arterial wall, HDL can deliver its CE to the liver by selective uptake via SR-BI and possibly also CETP (ie, direct pathway),33 or after CETP-mediated transfer of CE to apoB-containing lipoproteins that are subsequently taken up by the liver (ie, indirect pathway) (see Figure). Inhibition of CETP will reduce the indirect pathway and may thus compromise the overall flux of HDL cholesterol to the liver. In fact, a recent kinetic analysis study in humans indicated that not HDL but apoB-containing lipoproteins account for the clearance of CE from the circulation.34 In addition, a recent study indicated that plasma CETP may directly mediate the hepatic uptake of HDL-CE, independent of the LDL receptor or SR-BI.33 Therefore, elevation of HDL by inhibition of CETP may reduce the delivery of HDL-derived CE to the liver. This concern is underscored by the observation that CETP inhibition generally results in the accumulation of relatively large HDL particles, which may be less effective in accepting cholesterol from peripheral tissues.35 In this regard, it may be noted that such large HDL are associated with increased atherosclerosis in SR-BI knock out mice.36
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In this issue of Atherosclerosis, Thrombosis, and Vascular Biology, Kee et al37 have addressed the question whether CETP inhibition will compromise the overall removal of HDL-CE from plasma. Hereto, rabbits were fed a chow diet supplemented with an oral CETP inhibitor that resembles torcetrapib with respect to enhancing the association of CETP with its substrates, thereby creating a nonproductive CETP-lipoprotein complex. The CETP inhibitor (5 mg/kg) resulted in a strong decrease in CETP activity (&90%) and an increase in HDL cholesterol (&100%) and apoAI (&60%). By compartmental modeling of the decay curves resulting from intravenous injection of [3H]CE-labeled native HDL (nHDL) or reconstituted spherical HDL (rHDL), the authors determined the rate of HDL-CE removal from plasma via the direct pathway and indirect pathway. In untreated rabbits, the indirect pathway contributed 25% and 47% of the total HDL-CE removal, as judged from the fitted decay curves of nHDL and rHDL, respectively. As expected, CETP inhibition resulted in a virtually complete inhibition of the transfer of [3H]CE from HDL to apoB-containing lipoproteins. Concomitantly, the direct clearance pathway was increased by 18% (nHDL) or 65% (rHDL). These combined effects led to a total HDL-CE removal rate that was not significantly lower as observed in the untreated rabbits. The effects of CETP inhibition on HDL-CE fluxes are summarized in the accompanying figure.
Although Kee et al37 convincingly show that the direct pathway of HDL-CE removal is increased on CETP inhibition, the implication of this effect for RCT and atherosclerosis development should be interpreted with care for several reasons. First, although CETP inhibition does not affect the total HDL-CE removal rate significantly, a consistent trend toward reduction (13%) is observed using either nHDL or rHDL, which may reach statistical significance by using larger groups of rabbits. It should especially be noted that in the study using labeled autologous HDL (nHDL), which accurately reflects the behavior of the endogenous HDL-CE pool, the total HDL-CE removal rate under CETP-inhibited conditions (1.61 µmol/L per min) is just in between the values of the direct removal (1.37 µmol/L per min) and total removal (1.84 µmol/L per min) as observed in untreated rabbits. Second, by investigation of the impact of CETP inhibition on the serum clearance of HDL, the authors focus on only one of the final steps of RCT. It remains to be investigated whether CETP inhibition affects the uptake of cholesterol from extra-hepatic cells, and in particular from macrophages in the arterial wall. It is also not clear from this study whether the actual hepatic uptake of CE and subsequent fecal excretion of the cholesterol will be affected by CETP inhibition. A recent study in humans showed that CETP inhibition alone, by using torcetrapib, did not affect fecal excretion.38 However, in combination with atorvastatin, CETP inhibition resulted in a significantly reduced fecal output of bile acids (–16%) and neutral sterols (–8%).38 This is consistent with the recent observation that, in humans, apoB-containing lipoproteins are mainly responsible for the CE output via lipoproteins to the liver,34 and would imply that pharmacological CETP inhibition could indeed affect the normal uptake of CE via the LDL receptor pathway, which should be addressed by future studies.
In conclusion, Kee et al37 observed that CETP inhibition in rabbits does not necessarily decrease the overall removal rate of HDL-CE from plasma. However, the impact of this observation on RCT, including the critical efflux of cholesterol from the arterial wall, is still obscure. The effects of CETP inhibition on the integrative RCT from macrophages to the liver and feces in vivo, and on other functional parameters of HDL, including its antioxidant, antithrombotic, and antiinflammatory properties,39 should thus be subject of future investigation. In addition, given the recent evidence that the cholesterol output from plasma may differ between rabbits and humans,34 additional research will be required to elucidate whether these findings can be extrapolated to the clinical setting. The effects of CETP inhibition on (surrogate) cardiovascular end points in humans are eagerly awaited, and those data will ultimately indicate whether CETP inhibitors can become new powerful therapeutic tools for both raising HDL cholesterol and decreasing atherosclerosis, most likely in combination with drugs that lower apoB-containing lipoproteins, such as statins or fibrates.
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Acknowledgments |
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This work was supported by the Netherlands Organization for Scientific Research (NWO VIDI 917-36-351 to P.C.N.R.) and the Netherlands Heart Foundation (NHS 2003B136). We thank Jan Albert Kuivenhoven (Department of Experimental Vascular Medicine, Academic Medical Center, Amsterdam, The Netherlands) for critical reading of this manuscript.
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References |
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 Top References |
|---|
1. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet. 2002; 360: 7–22.[CrossRef][Medline] [Order article via Infotrieve]
2. LaRosa JC, Grundy SM, Waters DD, Shear C, Barter P, Fruchart JC, Gotto AM, Greten H, Kastelein JJ, Shepherd J, Wenger NK. Intensive lipid lowering with atorvastatin in patients with stable coronary disease. N Engl J Med. 2005; 352: 1425–1435.
3. Wilt TJ, Bloomfield HE, MacDonald R, Nelson D, Rutks I, Ho M, Larsen G, McCall A, Pineros S, Sales A. Effectiveness of statin therapy in adults with coronary heart disease. Arch Intern Med. 2004; 164: 1427–1436.
4. Gordon DJ, Rifkind BM. High-density lipoprotein–the clinical implications of recent studies. N Engl J Med. 1989; 321: 1311–1316.[Medline] [Order article via Infotrieve]
5. Genest JJ, McNamara JR, Salem DN, Schaefer EJ. Prevalence of risk factors in men with premature coronary artery disease. Am J Cardiol. 1991; 67: 1185–1189.[CrossRef][Medline] [Order article via Infotrieve]
6. Johnsen SH, Mathiesen EB, Fosse E, Joakimsen O, Stensland-Bugge E, Njolstad I, Arnesen E. Elevated high-density lipoprotein cholesterol levels are protective against plaque progression: a follow-up study of 1952 persons with carotid atherosclerosis the Tromso study. Circulation. 2005; 112: 498–504.
7. Bloomfield Rubins H, Davenport J, Babikian V, Brass LM, Collins D, Wexler L, Wagner S, Papademetriou V, Rutan G, Robins SJ. Reduction in stroke with gemfibrozil in men with coronary heart disease and low HDL cholesterol: The Veterans Affairs HDL Intervention Trial (VA-HIT). Circulation. 2001; 103: 2828–2833.
8. Barter PJ, Nicholls S, Rye KA, Anantharamaiah GM, Navab M, Fogelman AM. Antiinflammatory properties of HDL. Circ Res. 2004; 95: 764–772.
9. Lewis GF, Rader DJ. New insights into the regulation of HDL metabolism and reverse cholesterol transport. Circ Res. 2005; 96: 1221–1232.
10. Linsel-Nitschke P, Tall AR. HDL as a target in the treatment of atherosclerotic cardiovascular disease. Nat Rev Drug Discov. 2005; 4: 193–205.[CrossRef][Medline] [Order article via Infotrieve]
11. Duffy D, Rader DJ. Drugs in development: targeting high-density lipoprotein metabolism and reverse cholesterol transport. Curr Opin Cardiol. 2005; 20: 301–306.[CrossRef][Medline] [Order article via Infotrieve]
12. Meyers CD, Kashyap ML. Pharmacologic augmentation of high-density lipoproteins: mechanisms of currently available and emerging therapies. Curr Opin Cardiol. 2005; 20: 307–312.[CrossRef][Medline] [Order article via Infotrieve]
13. Dean BB, Borenstein JE, Henning JM, Knight K, Merz CN. Can change in high-density lipoprotein cholesterol levels reduce cardiovascular risk? Am Heart J. 2004; 147: 966–976.[CrossRef][Medline] [Order article via Infotrieve]
14. Birjmohun RS, Hutten BA, Kastelein JJ, Stroes ES. Efficacy and safety of high-density lipoprotein cholesterol-increasing compounds: a meta-analysis of randomized controlled trials. J Am Coll Cardiol. 2005; 45: 185–197.
15. Klerkx AH, de Grooth GJ, Zwinderman AH, Jukema JW, Kuivenhoven JA, Kastelein JJ. Cholesteryl ester transfer protein concentration is associated with progression of atherosclerosis and response to pravastatin in men with coronary artery disease (REGRESS). Eur J Clin Invest. 2004; 34: 21–28.[CrossRef][Medline] [Order article via Infotrieve]
16. Berthou L, Duverger N, Emmanuel F, Langouet S, Auwerx J, Guillouzo A, Fruchart JC, Rubin E, Denefle P, Staels B, Branellec D. Opposite regulation of human versus mouse apolipoprotein A-I by fibrates in human apolipoprotein A-I transgenic mice. J Clin Invest. 1996; 97: 2408–2416.[Medline] [Order article via Infotrieve]
17. Guerin M, Bruckert E, Dolphin PJ, Turpin G, Chapman MJ. Fenofibrate reduces plasma cholesteryl ester transfer from HDL to VLDL and normalizes the atherogenic, dense LDL profile in combined hyperlipidemia. Arterioscler Thromb Vasc Biol. 1996; 16: 763–772.
18. Jin FY, Kamanna VS, Kashyap ML. Niacin decreases removal of high-density lipoprotein apolipoprotein A-I but not cholesterol ester by Hep G2 cells. Implication for reverse cholesterol transport. Arterioscler Thromb Vasc Biol. 1997; 17: 2020–2028.
19. Meyers CD, Kamanna VS, Kashyap ML. Niacin therapy in atherosclerosis. Curr Opin Lipidol. 2004; 15: 659–665.[CrossRef][Medline] [Order article via Infotrieve]
20. Tall AR. Plasma cholesteryl ester transfer protein. J Lipid Res. 1993; 34: 1255–1274.[Medline] [Order article via Infotrieve]
21. Kuivenhoven JA, Jukema JW, Zwinderman AH, de Knijff P, McPherson R, Bruschke AV, Lie KI, Kastelein JJ. The role of a common variant of the cholesteryl ester transfer protein gene in the progression of coronary atherosclerosis. The Regression Growth Evaluation Statin Study Group. N Engl J Med. 1998; 338: 86–93.
22. Boekholdt SM, Kuivenhoven JA, Wareham NJ, Peters RJ, Jukema JW, Luben R, Bingham SA, Day NE, Kastelein JJ, Khaw KT. Plasma levels of cholesteryl ester transfer protein and the risk of future coronary artery disease in apparently healthy men and women: the prospective EPIC (European Prospective Investigation into Cancer and nutrition)-Norfolk population study. Circulation. 2004; 110: 1418–1423.
23. Hayek T, Masucci-Magoulas L, Jiang X, Walsh A, Rubin E, Breslow JL, Tall AR. Decreased early atherosclerotic lesions in hypertriglyceridemic mice expressing cholesteryl ester transfer protein transgene. J Clin Invest. 1995; 96: 2071–2074.[Medline] [Order article via Infotrieve]
24. Foger B, Chase M, Amar MJ, Vaisman BL, Shamburek RD, Paigen B, Fruchart-Najib J, Paiz JA, Koch CA, Hoyt RF, Brewer HB Jr, Santamarina-Fojo S. Cholesteryl ester transfer protein corrects dysfunctional high density lipoproteins and reduces aortic atherosclerosis in lecithin cholesterol acyltransferase transgenic mice. J Biol Chem. 1999; 274: 36912–36920.
25. Plump AS, Masucci-Magoulas L, Bruce C, Bisgaier CL, Breslow JL, Tall AR. Increased atherosclerosis in ApoE and LDL receptor gene knock-out mice as a result of human cholesteryl ester transfer protein transgene expression. Arterioscler Thromb Vasc Biol. 1999; 19: 1105–1110.
26. 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.
27. 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.
28. Brousseau ME, Schaefer EJ, Wolfe ML, Bloedon LT, Digenio AG, Clark RW, Mancuso JP, Rader DJ. Effects of an inhibitor of cholesteryl ester transfer protein on HDL cholesterol. N Engl J Med. 2004; 350: 1505–1515.
29. Clark RW, Sutfin TA, Ruggeri RB, Willauer AT, Sugarman ED, Magnus-Aryitey G, Cosgrove PG, Sand TM, Wester RT, Williams JA, Perlman ME, Bamberger MJ. Raising high-density lipoprotein in humans through inhibition of cholesteryl ester transfer protein: an initial multidose study of torcetrapib. Arterioscler Thromb Vasc Biol. 2004; 24: 490–497.
30. Zhong S, Sharp DS, Grove JS, Bruce C, Yano K, Curb JD, Tall AR. Increased coronary heart disease in Japanese-Am men with mutation in the cholesteryl ester transfer protein gene despite increased HDL levels. J Clin Invest. 1996; 97: 2917–2923.[Medline] [Order article via Infotrieve]
31. Okamoto H, Yonemori F, Wakitani K, Minowa T, Maeda K, Shinkai H. A cholesteryl ester transfer protein inhibitor attenuates atherosclerosis in rabbits. Nature. 2000; 406: 203–207.[CrossRef][Medline] [Order article via Infotrieve]
32. Huang Z, Inazu A, Nohara A, Higashikata T, Mabuchi H. Cholesteryl ester transfer protein inhibitor (JTT-705) and the development of atherosclerosis in rabbits with severe hypercholesterolaemia. Clin Sci (Lond). 2002; 103: 587–594.[Medline] [Order article via Infotrieve]
33. Gauthier A, Lau P, Zha X, Milne R, McPherson R. Cholesteryl ester transfer protein directly mediates selective uptake of high density lipoprotein cholesteryl esters by the liver. Arterioscler Thromb Vasc Biol. 2005; 25: 2177–2184.
34. Schwartz CC, VandenBroek JM, Cooper PS. Lipoprotein cholesteryl ester production, transfer, and output in vivo in humans. J Lipid Res. 2004; 45: 1594–1607.
35. Ishigami M, Yamashita S, Sakai N, Hirano K, Arai T, Maruyama T, Takami S, Koyama M, Kameda-Takemura K, Matsuzawa Y. High-density lipoproteins from probucol-treated patients have increased capacity to promote cholesterol efflux from mouse peritoneal macrophages loaded with acetylated low-density lipoproteins. Eur J Clin Invest. 1997; 27: 285–292.[CrossRef][Medline] [Order article via Infotrieve]
36. Van Eck M, Twisk J, Hoekstra M, Van Rij BT, Van der Lans CA, Bos IS, Kruijt JK, Kuipers F, Van Berkel TJ. Differential effects of scavenger receptor BI deficiency on lipid metabolism in cells of the arterial wall and in the liver. J Biol Chem. 2003; 278: 23699–23705.
37. Kee P, Caiazza D, Rye KA, Barrett PHR, Morehouse LA, Barter PJ. Effect of inhibiting cholesteryl ester transfer protein on the kinetics of high-density lipoprotein cholesteryl ester transport in plasma: in vivo studies in rabbits. Arterioscler Thromb Vasc Biol. 2006; 26: 884–890.
38. Brousseau ME, Diffenderfer MR, Millar JS, Nartsupha C, Asztalos BF, Welty FK, Wolfe ML, Rudling M, Bjorkhem I, Angelin B, Mancuso JP, Digenio AG, Rader DJ, Schaefer EJ. Effects of cholesteryl ester transfer protein inhibition on high-density lipoprotein subspecies, apolipoprotein A-I metabolism, and fecal sterol excretion. Arterioscler Thromb Vasc Biol. 2005; 25: 1057–1064.
39. Klerkx AH, El Harchaoui K, Van der Steeg WA, Boekholdt SM, Stroes ES, Kastelein JJ, Kuivenhoven JA. Cholesteryl ester transfer protein (CETP) inhibition beyond raising high-density lipoprotein cholesterol levels. Pathways by which modulation of CETP activity may alter atherogenesis. Arterioscler Thromb Vasc Biol. 2006; 26: 706–715.
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