Increasing HDL Cholesterol Levels
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《新英格兰医药杂志》
In the past decade, high-density lipoproteins (HDL) have emerged as a new potential therapeutic target for the treatment of cardiovascular disease. The key role of HDL as a carrier of excess cellular cholesterol in the reverse cholesterol transport pathway is believed to provide protection against atherosclerosis. In reverse cholesterol transport, peripheral tissues (e.g., vessel-wall macrophages) remove their excess cholesterol through the ATP-binding cassette transporter 1 (ABCA1) to poorly lipidated apolipoprotein A-I, forming pre--HDL. Lecithin–cholesterol acyltransferase then esterifies free cholesterol to cholesteryl esters, converting pre--HDL to mature spherical -HDL (see Figure).
Figure. Schematic Model of Reverse Cholesterol Transport Mediated by High-Density Lipoprotein (HDL), Resulting in an Increase in the Plasma HDL Level.
Triglycerides and cholesterol are transported by chylomicrons and remnant lipoproteins from the intestine and by very-low-density lipoproteins (VLDL) and low-density lipoproteins (LDL) from the liver (white arrows). Apolipoprotein A-I (apoA-I) is synthesized by the liver and, after interaction with hepatic ATP-binding cassette transporter 1 (ABCA1), is secreted into plasma as lipid-poor apolipoprotein A-I (yellow arrow). In reverse cholesterol transport, newly synthesized lipid-poor apolipoprotein A-I interacts with ABCA1, removing excess cellular cholesterol and forming pre--HDL (green arrow). Pre--HDL is converted into mature -HDL by lecithin–cholesterol acyltransferase (LCAT, black arrow). HDL cholesterol is returned to the liver through two pathways: selective uptake of cholesterol by the hepatic scavenger receptor, class B, type I (SR-BI, blue arrow), or the transfer of cholesteryl ester by cholesteryl ester transfer protein (CETP) to VLDL–LDL, with uptake by the liver through the LDL receptor (red arrows). Short-term HDL therapy to increase the HDL level and potentially provide protection against cardiovascular events can be achieved with the infusion of complexes consisting of apolipoprotein A-I Milano and phospholipids. Long-term increases in the HDL level and reductions in the LDL level result from the partial inhibition of CETP. FC denotes free cholesterol, PL phospholipids, LRP LDL-related protein, and LPL lipoprotein lipase.
HDL cholesterol is transported to the liver by two pathways: through the first pathway, it is delivered directly to the liver through interaction with the scavenger receptor, class B, type I (SR-BI); through the second pathway, cholesteryl esters in HDL are transferred by the cholesteryl ester transfer protein (CETP) to very-low-density lipoproteins (VLDL) and low-density lipoproteins (LDL) and are then returned to the liver through the LDL receptor. HDL cholesterol that is taken up by the liver is then excreted in the form of bile acids and cholesterol, completing the process of reverse cholesterol transport.1 HDL also decreases atherosclerosis by protecting LDL from oxidation.2 Oxidized or modified LDL, unlike normal LDL, is readily taken up by the macrophage scavenger receptor SR-A or CD36, resulting in the formation of foam cells. HDL may also slow the progression of lesions by selectively decreasing the production of endothelial cell–adhesion molecules that facilitate the uptake of cells into the vessel wall.3
Several lines of evidence support the concept that increasing the HDL level may provide protection against the development of atherosclerosis. Epidemiologic studies have shown an inverse correlation between HDL cholesterol levels and the risk of cardiovascular disease.1 Increasing the HDL cholesterol level by 1 mg may reduce the risk of cardiovascular disease by 2 to 3 percent. Overexpressing the apolipoprotein A-I gene in transgenic mice and rabbits and infusing complexes consisting of apolipoprotein A-I and phospholipids into hyperlipidemic rabbits increase HDL cholesterol levels and decrease the development of atherosclerosis.1 In humans, infusing either of these complexes or proapolipoprotein A-I results in short-term increases in HDL cholesterol, biliary cholesterol, and fecal sterol loss, reinforcing the concept that elevating the HDL cholesterol level decreases the risk of cardiovascular disease.1
Two different approaches to increasing the HDL cholesterol level that are currently under development are illustrated in the updated model of HDL and reverse cholesterol transport shown in the Figure. In a direct test of the atheroprotective effects of HDL, patients with established cardiovascular disease were given five weekly infusions of a complex consisting of apolipoprotein A-I Milano and phospholipids and were compared with controls by means of intravascular ultrasonography used to quantitate coronary atheroma. The total volume of atheroma decreased by 4.2 percent; this degree of regression in only six weeks was unexpected.4 The potential for significant reduction in atherosclerosis within a period of weeks rather than months led to a new concept: short-term HDL-infusion therapy, whereby patients with cardiovascular disease would receive infusions of HDL for six to eight weeks in conjunction with lipid therapy in order to reduce atherosclerosis and the risk of cardiac events in the short term. Additional approaches to short-term HDL therapy that are under development include the infusion of synthetic peptides based on the amphipathic structure of apolipoprotein A-I and the reinfusion of autologous delipidated HDL. Detailed data from clinical trials will now be required in order to establish definitively whether short-term therapy consisting of HDL infusions will provide protection against cardiovascular events.
A second approach to HDL therapy is the development of agents that would increase the HDL cholesterol level effectively for a long or indefinite period. The most advanced clinically tested agents that increase the HDL cholesterol level are CETP inhibitors, which simultaneously reduce the LDL cholesterol level (see Figure). As outlined above, CETP mediates the exchange of cholesteryl ester for triglycerides between HDL and VLDL–LDL and may be proatherogenic if the CETP-mediated VLDL–LDL cholesteryl ester is taken up by arterial macrophages, or may be antiatherogenic if this cholesteryl ester is returned to the liver through the LDL receptor by means of the pathway of reverse cholesterol transport that is initiated by HDL.5
The partial inhibition of CETP activity with the use of either antisense oligodeoxynucleotides or anti-CETP antibodies in rabbits that have been fed cholesterol increases the HDL cholesterol level and decreases aortic atherosclerosis.5 The administration of a chemical CETP inhibitor, JTT-705, to cholesterol-fed rabbits resulted in a doubling of the HDL cholesterol level, a 50 percent decrease in the levels of non-HDL cholesterol, and a 70 percent decrease in atherosclerosis. In contrast, patients in whom CETP activity is completely absent have large, cholesterol-enriched, dysfunctional HDL particles with decreased capacity to remove cellular cholesterol, as well as decreased plasma levels of heterogeneous LDL, and have been reported to be at risk for cardiovascular disease.5 These findings indicate that partial inhibition of CETP may be atheroprotective but the complete absence of CETP activity can create a proatherogenic lipid profile.
In this issue of the Journal, Brousseau et al. (pages 1505–1515) report a single-blind study of the effects of the CETP inhibitor torcetrapib, alone or in combination with 20 mg of atorvastatin, on the lipoprotein phenotype in 19 subjects with a low HDL cholesterol level. Subjects received torcetrapib for four weeks at a dose of 120 mg, either alone or in combination with atorvastatin, and a subgroup of subjects in the torcetrapib-alone group then received 120 mg of torcetrapib twice daily for an additional four weeks. The HDL cholesterol level increased by 46 percent in the group that received torcetrapib alone for four weeks, by 61 percent in the group that received torcetrapib plus atorvastatin for four weeks, and by 106 percent in the subgroup that received the additional four weeks of torcetrapib treatment; the LDL cholesterol level decreased by 17 percent, 8 percent, and 17 percent in the three groups, respectively. Torcetrapib therapy was well tolerated, and there were no major adverse events. With torcetrapib therapy, HDL and LDL particles increased in size. Since CETP activity was only partially inhibited in this study (by 28 to 65 percent), the formation of the potentially proatherogenic large HDL particles and the heterogeneous LDL particles that are characteristic of lipoproteins in CETP-deficient patients was avoided. Despite the small number of patients, the results suggest that torcetrapib can effectively increase the HDL cholesterol level in subjects with low levels; moreover, the addition of torcetrapib to statin therapy is associated with a further reduction in the LDL cholesterol level.
Additional clinical trials will be required to confirm the effects of torcetrapib on plasma lipoproteins, to select the right dose for clinical use, and to establish whether CETP inhibitors will provide protection against cardiovascular disease. Given the available data, CETP inhibitors hold great promise as a new class of drugs that will be of major benefit in the treatment of cardiovascular disease.
The development of drugs to increase HDL cholesterol levels for either the short term or the long term represents an exciting new approach to the treatment of high-risk patients with cardiovascular disease. The combined use of statins and CETP inhibitors has the potential for markedly improving our effectiveness in reducing the risk of cardiac events in patients with cardiovascular disease.
Dr. Brewer reports having served as a consultant to and a member of the speakers' bureau of Pfizer, Esperion, and Lipid Sciences.
Source Information
From the National Heart, Lung, and Blood Institute, Bethesda, Md.
References
Brewer HB Jr. High-density lipoprotein: a new potential therapeutic target for the prevention of cardiovascular disease. Arterioscler Thromb Vasc Biol 2004;24:387-391.
Navab M, Anantharamaiah GM, Hama S, et al. Oral administration of an Apo A-I mimetic peptide synthesized from D-amino acids dramatically reduces atherosclerosis in mice independent of plasma cholesterol. Circulation 2002;105:290-292.
Barter PJ, Baker PW, Rye KA. Effect of high-density lipoproteins on the expression of adhesion molecules in endothelial cells. Curr Opin Lipid 2002;13:285-8.
Nissen SE, Tsunoda T, Tuzcu EM, et al. Effect of recombinant ApoA-I Milano on coronary atherosclerosis in patients with acute coronary syndromes: a randomized controlled trial. JAMA 2003;290:2292-2300.
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.(H. Bryan Brewer, Jr., M.D)
Figure. Schematic Model of Reverse Cholesterol Transport Mediated by High-Density Lipoprotein (HDL), Resulting in an Increase in the Plasma HDL Level.
Triglycerides and cholesterol are transported by chylomicrons and remnant lipoproteins from the intestine and by very-low-density lipoproteins (VLDL) and low-density lipoproteins (LDL) from the liver (white arrows). Apolipoprotein A-I (apoA-I) is synthesized by the liver and, after interaction with hepatic ATP-binding cassette transporter 1 (ABCA1), is secreted into plasma as lipid-poor apolipoprotein A-I (yellow arrow). In reverse cholesterol transport, newly synthesized lipid-poor apolipoprotein A-I interacts with ABCA1, removing excess cellular cholesterol and forming pre--HDL (green arrow). Pre--HDL is converted into mature -HDL by lecithin–cholesterol acyltransferase (LCAT, black arrow). HDL cholesterol is returned to the liver through two pathways: selective uptake of cholesterol by the hepatic scavenger receptor, class B, type I (SR-BI, blue arrow), or the transfer of cholesteryl ester by cholesteryl ester transfer protein (CETP) to VLDL–LDL, with uptake by the liver through the LDL receptor (red arrows). Short-term HDL therapy to increase the HDL level and potentially provide protection against cardiovascular events can be achieved with the infusion of complexes consisting of apolipoprotein A-I Milano and phospholipids. Long-term increases in the HDL level and reductions in the LDL level result from the partial inhibition of CETP. FC denotes free cholesterol, PL phospholipids, LRP LDL-related protein, and LPL lipoprotein lipase.
HDL cholesterol is transported to the liver by two pathways: through the first pathway, it is delivered directly to the liver through interaction with the scavenger receptor, class B, type I (SR-BI); through the second pathway, cholesteryl esters in HDL are transferred by the cholesteryl ester transfer protein (CETP) to very-low-density lipoproteins (VLDL) and low-density lipoproteins (LDL) and are then returned to the liver through the LDL receptor. HDL cholesterol that is taken up by the liver is then excreted in the form of bile acids and cholesterol, completing the process of reverse cholesterol transport.1 HDL also decreases atherosclerosis by protecting LDL from oxidation.2 Oxidized or modified LDL, unlike normal LDL, is readily taken up by the macrophage scavenger receptor SR-A or CD36, resulting in the formation of foam cells. HDL may also slow the progression of lesions by selectively decreasing the production of endothelial cell–adhesion molecules that facilitate the uptake of cells into the vessel wall.3
Several lines of evidence support the concept that increasing the HDL level may provide protection against the development of atherosclerosis. Epidemiologic studies have shown an inverse correlation between HDL cholesterol levels and the risk of cardiovascular disease.1 Increasing the HDL cholesterol level by 1 mg may reduce the risk of cardiovascular disease by 2 to 3 percent. Overexpressing the apolipoprotein A-I gene in transgenic mice and rabbits and infusing complexes consisting of apolipoprotein A-I and phospholipids into hyperlipidemic rabbits increase HDL cholesterol levels and decrease the development of atherosclerosis.1 In humans, infusing either of these complexes or proapolipoprotein A-I results in short-term increases in HDL cholesterol, biliary cholesterol, and fecal sterol loss, reinforcing the concept that elevating the HDL cholesterol level decreases the risk of cardiovascular disease.1
Two different approaches to increasing the HDL cholesterol level that are currently under development are illustrated in the updated model of HDL and reverse cholesterol transport shown in the Figure. In a direct test of the atheroprotective effects of HDL, patients with established cardiovascular disease were given five weekly infusions of a complex consisting of apolipoprotein A-I Milano and phospholipids and were compared with controls by means of intravascular ultrasonography used to quantitate coronary atheroma. The total volume of atheroma decreased by 4.2 percent; this degree of regression in only six weeks was unexpected.4 The potential for significant reduction in atherosclerosis within a period of weeks rather than months led to a new concept: short-term HDL-infusion therapy, whereby patients with cardiovascular disease would receive infusions of HDL for six to eight weeks in conjunction with lipid therapy in order to reduce atherosclerosis and the risk of cardiac events in the short term. Additional approaches to short-term HDL therapy that are under development include the infusion of synthetic peptides based on the amphipathic structure of apolipoprotein A-I and the reinfusion of autologous delipidated HDL. Detailed data from clinical trials will now be required in order to establish definitively whether short-term therapy consisting of HDL infusions will provide protection against cardiovascular events.
A second approach to HDL therapy is the development of agents that would increase the HDL cholesterol level effectively for a long or indefinite period. The most advanced clinically tested agents that increase the HDL cholesterol level are CETP inhibitors, which simultaneously reduce the LDL cholesterol level (see Figure). As outlined above, CETP mediates the exchange of cholesteryl ester for triglycerides between HDL and VLDL–LDL and may be proatherogenic if the CETP-mediated VLDL–LDL cholesteryl ester is taken up by arterial macrophages, or may be antiatherogenic if this cholesteryl ester is returned to the liver through the LDL receptor by means of the pathway of reverse cholesterol transport that is initiated by HDL.5
The partial inhibition of CETP activity with the use of either antisense oligodeoxynucleotides or anti-CETP antibodies in rabbits that have been fed cholesterol increases the HDL cholesterol level and decreases aortic atherosclerosis.5 The administration of a chemical CETP inhibitor, JTT-705, to cholesterol-fed rabbits resulted in a doubling of the HDL cholesterol level, a 50 percent decrease in the levels of non-HDL cholesterol, and a 70 percent decrease in atherosclerosis. In contrast, patients in whom CETP activity is completely absent have large, cholesterol-enriched, dysfunctional HDL particles with decreased capacity to remove cellular cholesterol, as well as decreased plasma levels of heterogeneous LDL, and have been reported to be at risk for cardiovascular disease.5 These findings indicate that partial inhibition of CETP may be atheroprotective but the complete absence of CETP activity can create a proatherogenic lipid profile.
In this issue of the Journal, Brousseau et al. (pages 1505–1515) report a single-blind study of the effects of the CETP inhibitor torcetrapib, alone or in combination with 20 mg of atorvastatin, on the lipoprotein phenotype in 19 subjects with a low HDL cholesterol level. Subjects received torcetrapib for four weeks at a dose of 120 mg, either alone or in combination with atorvastatin, and a subgroup of subjects in the torcetrapib-alone group then received 120 mg of torcetrapib twice daily for an additional four weeks. The HDL cholesterol level increased by 46 percent in the group that received torcetrapib alone for four weeks, by 61 percent in the group that received torcetrapib plus atorvastatin for four weeks, and by 106 percent in the subgroup that received the additional four weeks of torcetrapib treatment; the LDL cholesterol level decreased by 17 percent, 8 percent, and 17 percent in the three groups, respectively. Torcetrapib therapy was well tolerated, and there were no major adverse events. With torcetrapib therapy, HDL and LDL particles increased in size. Since CETP activity was only partially inhibited in this study (by 28 to 65 percent), the formation of the potentially proatherogenic large HDL particles and the heterogeneous LDL particles that are characteristic of lipoproteins in CETP-deficient patients was avoided. Despite the small number of patients, the results suggest that torcetrapib can effectively increase the HDL cholesterol level in subjects with low levels; moreover, the addition of torcetrapib to statin therapy is associated with a further reduction in the LDL cholesterol level.
Additional clinical trials will be required to confirm the effects of torcetrapib on plasma lipoproteins, to select the right dose for clinical use, and to establish whether CETP inhibitors will provide protection against cardiovascular disease. Given the available data, CETP inhibitors hold great promise as a new class of drugs that will be of major benefit in the treatment of cardiovascular disease.
The development of drugs to increase HDL cholesterol levels for either the short term or the long term represents an exciting new approach to the treatment of high-risk patients with cardiovascular disease. The combined use of statins and CETP inhibitors has the potential for markedly improving our effectiveness in reducing the risk of cardiac events in patients with cardiovascular disease.
Dr. Brewer reports having served as a consultant to and a member of the speakers' bureau of Pfizer, Esperion, and Lipid Sciences.
Source Information
From the National Heart, Lung, and Blood Institute, Bethesda, Md.
References
Brewer HB Jr. High-density lipoprotein: a new potential therapeutic target for the prevention of cardiovascular disease. Arterioscler Thromb Vasc Biol 2004;24:387-391.
Navab M, Anantharamaiah GM, Hama S, et al. Oral administration of an Apo A-I mimetic peptide synthesized from D-amino acids dramatically reduces atherosclerosis in mice independent of plasma cholesterol. Circulation 2002;105:290-292.
Barter PJ, Baker PW, Rye KA. Effect of high-density lipoproteins on the expression of adhesion molecules in endothelial cells. Curr Opin Lipid 2002;13:285-8.
Nissen SE, Tsunoda T, Tuzcu EM, et al. Effect of recombinant ApoA-I Milano on coronary atherosclerosis in patients with acute coronary syndromes: a randomized controlled trial. JAMA 2003;290:2292-2300.
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.(H. Bryan Brewer, Jr., M.D)