1975] Cholesterol in the year 2000. The gatekeeper for eliminating excess tissue cholesterol. Lipids. Alcohol consumption stimulates early steps in reverse cholesterol transport. Metabolism. Metabolism. [Metabolism. [Am Heart J. 2004]. J Cardiovasc Risk. 1997] Intravenous apoA-I/lecithin discs increase pre-beta-HDL concentration in tissue fluid and stimulate reverse cholesterol transport in humans.

2008 February; 4 (1) : 39?57. PMCID: PMC2464766

Navin K Kapur, Dominique Ashen, and Roger S Blumenthal

HDL-.C and coronary heart disease. Phase one: nascent HDL-.C acquires free cholesterol. Phase two: lecithin: acyl CoA transferase (LCAT) esterifies free cholesterol. Phase four: HDL-.C catabolism.

Phase three: cholesterol ester transfer protein (CETP) mediates exchange of cholesterol esters between HDL-.C and Apo B lipoproteins. Phase four: HDL-.C catabolism. Pleiotropic effects of HDL-.C: beyond RCT. Approaches to raising HDL-.C levels: lifestyle modifictions. Approaches to raising HDL-.C levels: standard pharmacotherapy. Approaches to raising HDL-.C levels: emerging therapeutics.

Summary. References. Introduction In the early 1900s, a German chemist named Adolph Windaus determined atheromatous plaque from human aortas contained 20-fold higher concentrations of cholesterol than normal aortas. In 1955, a biophysicist named John Gofman used ultracentrifugation to separate plasma lipoproteins by density and correlated risk of myocardial infarction (MI) with elevated low-density lipoprotein cholesterol (LDL-C) levels.

Since the first Adult Treatment Panel (ATP) recommendations in 1988 [ Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel II) 1993 ], guidelines have increasingly focused on aggressive management of elevated LDL-C in populations at risk for CHD.

Moreover, nearly 15% of patients with acute myocardial infarction (MI) have LDL-C levels less than 100 mg/dL at presentation ( Forrester et al 2005 ), suggesting that previously cited LDL-C targets remain too high or the benefit of very aggressive LDL-C lowering is quite limited. The Treating to New Targets (TNT) trial ( LaRosa et al 2005 ) showed a 2.2% absolute and a 22% relative risk reduction for major cardiovascular events in patients receiving high dose compared to low dose atorvastatin.

The mean LDL-C levels were 77 mg/dL in the high dose statin group versus 100 mg/dL in the low dose statin group. Thus, while great emphasis has been placed on the importance of LDL-C lowering in CVD risk reduction, there is growing interest directed at raising HDL-C levels for further risk reduction. . At present, no approved therapies increase HDL-C levels by any comparable magnitude to therapies designed to lower LDL-C levels.

This review provides a detailed update on HDL-C as a therapeutic target for CVD risk reduction. ......  Other Sections? .. Abstract. Introduction. HDL-.C and coronary heart disease. HDL-.C metabolism and reverse cholesterol transport (RCT). Phase two: lecithin: acyl CoA transferase (LCAT) esterifies free cholesterol.

HDL-C and coronary heart disease

Lovastatin decreased both TC and LDL-C levels by 18% and 25%, respectively, while increasing HDL-C levels by 6%. After more than 5 years of follow-up, the absolute risk in the primary composite end point of fatal or non-fatal MI, unstable angina, or sudden cardiac death was reduced in absolute terms by 2.2% in men and 1.2% in women with a relative risk reduction of 37%. This study was the first primary prevention study to show that individuals with HDL-C &x0003c;40 mg/dL received the greatest benefit, suggesting the lower cutpoint HDL-C of 35 mg/dL in ATP II should be raised to 40 mg/dL in ATP III.

These clinical trials confirm an increased risk associated with low serum levels of HDL-C and the beneficial effects of pharmacotherapy in adults with low HDL-C in primary prevention. . Patients with manifest CHD also benefit from raising HDL-C and lowering TG. The Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial (VA-HIT) compared treatment with gemfibrozil versus placebo in more than 2500 men with established CHD, average LDL-C levels (&x0003c;140 mg/dL), and low HDL-C levels (&x0003c;40 mg/dL).

After a mean follow-up of 5 years, gemfibrozil decreased TG levels by 31% and increased HDL-C levels by 6%, while levels of LDL-C remained quantitatively unchanged; there was a relative risk reduction of 22% (17.3% vs 21.7% p &x0003c; 0.006) in CHD death and non-fatal MI in the treatment group. Gemfibrozil therapy was associated with a 24% relative risk reduction in the composite end point of nonfatal MI, stroke, and CHD death (p &x0003c; 0.001) ( Rubins et al 2001 ).

. The Scandanavian Simvastatin Survival Study Group (4S) was a large, randomized, placebo-controlled trial evaluating simvastatin (20&x02013;40 mg/day) in 4444 men and women aged 35&x02013;70 years over a median follow-up period of 5.4 years. Simvastatin therapy decrease TC and LDL-C (25% and 35%, respectively) and increased HDL-C by 8% compared to placebo. Simvastatin treatment resulted in a 30% relative risk reduction in overall mortality (8.2% vs 11.5%, p = 0.0003) and reduced non-fatal MI, ischemic heart disease death, and coronary revascularization ( Scandinavian Simvastatin Survival Study Group 1994 ).

. The Bezafibrate Infarction Prevention Study (BIPS) was a blinded, placebo-controlled trial of bezafibrate therapy in 3122 patients with previous MI or angina pectoris and baseline LDL-C &x0003c;180 mg/dL, HDL-C &x0003c;45 mg/dL, and TG &x0003c;300 mg/dL. At 5&x02013;7 years of follow-up, bezafibrate increased HDL-C more than 15% and decreased TG levels by 25%. The overall relative reduction in the primary end point of 9% was not statistically significant; however, a 40% relative risk reduction was observed in patients with baseline TG &x0003e;200 mg/dL, suggesting fibrates may be beneficial in patients with known CAD and elevated TG levels ( Kaplinsky 1998 ).

. Based on the epidemiologic data available, the NCEP ATP III guidelines raised the cut-point for low HDL-C levels from 35 mg/dL to 40 mg/dL, thereby identifying a larger number of adults at risk for developing CHD. Current guidelines define &x0201c;high&x0201d; HDL-C levels as above 60 mg/dL ( Grundy et al 2004 ). The definition of &x0201c;optimal&x0201d; HDL-C will likely undergo further modification as data becomes available.

......  Other Sections? .. Abstract. Introduction. HDL-.C and coronary heart disease. Phase one: nascent HDL-.C acquires free cholesterol. Phase two: lecithin: acyl CoA transferase (LCAT) esterifies free cholesterol. Phase three: cholesterol ester transfer protein (CETP) mediates exchange of cholesterol esters between HDL-.C and Apo B lipoproteins. Phase four: HDL-.C catabolism.

Pleiotropic effects of HDL-.C: beyond RCT. Approaches to raising HDL-.C levels: lifestyle modifictions. Approaches to raising HDL-.C levels: standard pharmacotherapy. Approaches to raising HDL-.C levels: emerging therapeutics. Summary. HDL-C metabolism and reverse cholesterol transport (RCT) In animal studies, exogenous infusions of HDL-C or apolipoprotein A-1 (Apo AI), the major apolipoprotein associated with HDL-C, prevents atherosclerosis from developing or progressing ( Badimon et al 1990 ; Duverger et al 1996 ).

HDL-C is a macromolecule containing lipids and proteins that transport water-insoluble fats in blood. A phospholipid (PL) monolayer containing free cholesterol (FC) and apolipoproteins (Apo) surrounds a non-polar lipid core containing FC and TG. Apo AI and AII are the major protein components of HDL-C. While Apo AI is ubiquitously associated with HDL-C, Apo AII is found in about 60% of HDL-C molecules ( Lewis et al 2005 ).

HDL-C mediated reverse cholesterol transport. Reverse cholesterol transport (RCT) can be divided into four phases. 1) transfer of free cholesterol (FC) to pre-b HDL via ABCA1, 2) esterification of surface-associated FC by the enzyme Lecithin:acyl CoA (more )  Other Sections? Abstract. Introduction. HDL-.C and coronary heart disease. HDL-.C metabolism and reverse cholesterol transport (RCT).

Phase two: lecithin: acyl CoA transferase (LCAT) esterifies free cholesterol. Phase three: cholesterol ester transfer protein (CETP) mediates exchange of cholesterol esters between HDL-.C and Apo B lipoproteins. Phase four: HDL-.C catabolism. Pleiotropic effects of HDL-.C: beyond RCT. Approaches to raising HDL-.C levels: lifestyle modifictions. Approaches to raising HDL-.C levels: standard pharmacotherapy.

Approaches to raising HDL-.C levels: emerging therapeutics. Summary. Phase one: nascent HDL-C acquires free cholesterol The nascent form of circulating HDL-C rich in Apo AI, termed discoidal pre-&x003b2; HDL, removes FC and PL from peripheral cells throughout the body by interacting with a membrane associated protein ubiquitously expressed in peripheral tissues, known as ATP-binding cassette transporter 1 (ABCA1).

Pre-&x003b2; HDL is rich in Apo AI and serves as a template for the generation of lipid-rich HDL-C ( Sviridov et al 2002 ). Pre-&x003b2; HDL is generated by either de novo secretion from hepatocytes or the intestinal mucosa, direct dissociation from chylomicrons and very low density lipoprotein (VLDL) mediated by lipoprotein lipase (LL), or as a by-product of HDL-C particle interconversion ( Kwiterovich 1998 ).

. Once generated, pre-&x003b2; HDL receives PL and FC from peripheral cells by associating with the surface protein ABCA1 ( Oram and Lawn 2001 ), which is expressed by the liver and intestinal mucosa. Patients with Tangier Disease, an autosomal recessive disorder characterized by two non-functional ABCA1 alleles and extremely low levels of HDL-C, exemplify the significance of ABCA1 in HDL-C metabolism ( Bodzioch et al 1999 ).

Heterozygous individuals with a partial reduction in functional ABCA1 have a corresponding 50% decrease in serum HDL-C levels ( Marcil et al 1999 ). . Animal models further support the critical role of ABCA1 in RCT. ABCA1-deficient mice generated by targeted gene ablation in DBA-1J embryonic stem cells demonstrated a 99.5% and 99.8% reduction in serum HDL-C and Apo AI levels, respectively.

In this model, loss of ABCA1 correlated with increased accumulation of lipid-laden macrophages, an integral component of atherosclerotic plaque ( McNeish et al 2000 ). Conversely, overexpression of ABCA1 in transgenic mice is associated with increased TC, HDL-C levels, and Apo AI with enhanced cholesterol efflux and reduced levels of atherogenesis ( Brewer et al 2004 ). Finally, crossing transgenic mice overexpressing ABCA1 with athero-susceptible transgenic mice, such as LDL receptor (LDLr) or Apolipoprotein E knockout (KO) models, reduced atheromatous progression ( Joyce et al 2003 ).

. ABCG1 is another member of the ATP-binding cassette family that promotes efflux of PL and FC from macrophages to mature HDL-C rather than pre-&x003b2; HDL ( Kennedy et al 2005 ) Macrophages deficient in ABCG1 also have impaired FC efflux and accumulate excess cholesterol ( Out R 2006 ). Taken together, these data suggest that both ABCA1 and ABCG1 are potential therapeutic targets to raise HDL-C and promote RCT.

. Transcription of both ABCA1 and ABCG1 is regulated by members of a steroid superfamily of nuclear receptors known as the Liver X receptor/Retinoid X receptor (LXR/RXR) heterodimer. When activated by oxysterols from FC this heterodimer stimulates ABCA1 and ABCG1 gene expression, thereby enhancing cholesterol efflux ( Vaughan and Oram 2005 ; Venkateswaran et al 2000 ). The heterodimer is also regulated by the activity of peroxisome proliferator-activated receptors (PPAR) &x003b1; and &x003b3;, which are closely linked to insulin resistance and the metabolic syndrome ( Anderson et al 2004 ).

PPAR-&x003b1; and PPAR-&x003b3; agonists have been shown to upregulate LXR and ABCA1 expression and promote macrophage cholesterol efflux ( Schmitz et al 2002 ; Chawla et al 2001 ). Introduction. HDL-.C and coronary heart disease. HDL-.C metabolism and reverse cholesterol transport (RCT). Phase three: cholesterol ester transfer protein (CETP) mediates exchange of cholesterol esters between HDL-.C and Apo B lipoproteins.

Phase four: HDL-.C catabolism.

Newly acquired FC undergoes esterfication to form cholesteryl esters (CE) which migrate to the center of the discoidal pre-beta HDL molecule. The spherical morphology of mature &x003b1;-HDL-C promotes further HDL-C metabolism and cholesterol efflux ( Wang and Briggs 2004 ).

Introduction. HDL-.C and coronary heart disease. Phase one: nascent HDL-.C acquires free cholesterol. Phase two: lecithin: acyl CoA transferase (LCAT) esterifies free cholesterol. Phase three: cholesterol ester transfer protein (CETP) mediates exchange of cholesterol esters between HDL-.C and Apo B lipoproteins. Phase four: HDL-.C catabolism. Pleiotropic effects of HDL-.C: beyond RCT.

Approaches to raising HDL-.C levels: lifestyle modifictions. Approaches to raising HDL-.C levels: standard pharmacotherapy. Approaches to raising HDL-.C levels: emerging therapeutics. Summary. References. The enzyme cholesteryl ester transfer protein (CETP) exchanges CE from HDL-C for TG in LDL-C and VLDL.

A nested case control study known as the European Prospective Investigation into Cancer and nutrition (EPIC)-Norfolk cohort study suggested an increased CHD risk in patients with elevated TG and elevated CETP levels ( Boekholdt et al 2004 ).

Dual nature of CETP activity. By shuttling cholesteryl esters (CE) and triglycerides (TG) between HDL-C and Apo B-associated lipoproteins, the enzyme cholesteryl ester transfer protein (CETP) creates substrate for both pro-atherogenic and anti-atherogenic (more ) However, complete abolition of CETP activity results in large, cholesterol-laden, dysfunctional HDL-C with reduced cholesterol efflux RCT capacity ( Yamashita et al 1988 ; Sakai et al 1991 ; Ikewaki et al 1995 ).

Furthermore, CETP activity may be anti-atherogenic if CE-laden lipoproteins are bound by the LDLr for hepatic uptake and excretion. CETP activity may promote RCT by stimulating LCAT activity and regenerating pre-&x003b2; HDL ( Brewer et al 2004 ). Introduction. HDL-.C and coronary heart disease. HDL-.C metabolism and reverse cholesterol transport (RCT). Phase two: lecithin: acyl CoA transferase (LCAT) esterifies free cholesterol.

Phase three: cholesterol ester transfer protein (CETP) mediates exchange of cholesterol esters between HDL-.C and Apo B lipoproteins. Phase four: HDL-.C catabolism.

Introduction. HDL-.C and coronary heart disease. Phase one: nascent HDL-.C acquires free cholesterol. Phase two: lecithin: acyl CoA transferase (LCAT) esterifies free cholesterol.

The major anti-oxidant effects of HDL-C are mediated by two associated enzymes paroxonase (PON) and platelet-activating factor acetylhydrolase (PAFAH) ( Graham et al 1997 ). PON, an arylesterase enzyme carried by Apo AI, inhibits oxidation of LDL-C ( Mackness et al 2000 ). LDLr-null mice lacking PON are susceptible to organophosphate toxicity and manifest accelerated atherosclerosis ( Shih et al 1998 ).

PAF promotes cell adhesion, platelet aggregation, and vascular permeability. HDL-C inhibits PAF production by endothelial cells in dose-dependent manner ( Sugatani et al 1996 ) via hydrolysis of acetyl residues mediated by PAFAH. Genetic polymorphisms of the enzyme PAFAH have been associated with an increased risk of acute MI ( Liu et al 2006 ).

In patients with known CAD, elevation of HDL-C levels via pharmacologic therapy improves endothelial function ( O&x02019;Connell et al 2001 ). In patients with CHD, HDL-C levels correlate positively with coronary vasomotor tone ( Zeiher et al 1994 ). In vitro, HDL-C enhances endothelial nitric oxide synthase (eNOS) activity ( Kuvin et al 2002 ). The mechanism of HDL-C mediated eNOS activation remains unknown, however may involve an interaction between endothelial SR-B1 and Apo AI ( Yuhanna et al 2001 ).

HDL-C inhibits endothelial apoptosis induced by TNF-&x003b1; in a dose-dependent manner by inhibiting caspase 3 activity ( Sugano et al 2000 ).

HDL-C is also associated with anti-thrombotic and profibrinolytic effects. HDL-C inhibits platelet aggregation by blocking thromboxane-A2 (TXA2) and PAF activity, while stimulating nitric oxide (NO) and PGI2 synthesis ( Saku et al 1985 ; Naqvi et al 1999 ). In the Atherosclerosis Risk in Communities (ARIC) study, HDL-C levels inversely correlated with circulating von Willebrand factor (vWF) levels, suggesting that HDL-C may prevent synthesis of this pro-thrombotic protein.

HDL-C also enhances the anti-thrombotic activity of protein C and protein S ( Griffin et al 1999 ).

Introduction. HDL-.C and coronary heart disease. HDL-.C metabolism and reverse cholesterol transport (RCT). Phase two: lecithin: acyl CoA transferase (LCAT) esterifies free cholesterol. Phase three: cholesterol ester transfer protein (CETP) mediates exchange of cholesterol esters between HDL-.C and Apo B lipoproteins. Phase four: HDL-.C catabolism. Pleiotropic effects of HDL-.C: beyond RCT.

Approaches to raising HDL-.C levels: lifestyle modifictions. Approaches to raising HDL-.C levels: standard pharmacotherapy. Approaches to raising HDL-.C levels: emerging therapeutics. Summary. References. Approaches to raising HDL-C levels: lifestyle modifictions Numerous studies associate excess body weight with higher TC, LDL-C, and TG levels and lower HDL-C levels. A meta-analysis of 70 studies examining the effects of weight reduction on lipid profiles published between 1966 and 1989 demonstrated a 1 mg/dL increase in HDL-C for every 3 kg of weight lost ( Dattilo et al 1992 ).

A one-year randomized controlled study evaluating weight loss on plasma lipid profiles in 131 overweight sedentary men demonstrated a significant increase in plasma HDL-C levels (44 mg/dL with exercise, 47 mg/dL with diet, versus 40 mg/dL in controls; p &x0003c; 0.01), while LDL-C levels remained unchanged (Wood et al 1998). . As a means to reducing weight, regular aerobic exercise increases HDL-C by 10%&x02013;20% on average in sedentary adults ( Williams 1997 ).

Previous studies report an increase in HDL-C levels by 1 mg/dL for every 4 to 5 miles run per week (ie, 49 mg/dL with 5 miles (8 km) run per week, 51 mg/dL with 9 miles (15) run per week, 53 mg/dL with 12 miles (20 km) run per week, and 57 mg/dL with 31 miles (50 km) run per week; p &x0003c; 0.001 versus non-runners) ( Kokkinos et al 1995 ). While exercise quantity and intensity differ between studies, the duration of aerobic exercise rather than intensity appears to have a greater impact on HDL-C levels ( Durstine et al 2001 ).

. Variable changes in HDL-C have been observed in response to exercise. Some individuals significantly increase HDL-C levels after 8 weeks of regular aerobic exercise (running), while other individuals may not manifest changes in HDL-C for nearly 2 years ( Durstine et al 2001 ). In another study, no significant change in HDL-C was observed in adults with low HDL-C and moderately elevated LDL-C after 6 weeks of walking or jogging 10 miles (16 km) per week ( Stefanick et al 1998 ).

Moreover, women appear to experience greater improvement in HDL-C with cardiac rehabilitation than men ( Savage et al 2004 ). In general, HDL-C increases with exercise supporting the recommendation of a program of regular, brisk aerobic exercise program most days of the week ( US Department of Health and Human Services 1999 ). The mechanisms, by which exercise and reduced weight increase HDL-C likely involves enchanced lipoprotein lipase (LL) activity, increased RCT, and increased levels of pre-&x003b2; HDL ( Gupta et al 1993 ; Sviridov et al 2003 ).

... Dietary modifications.. Major dietary influences on HDL-C levels include total fat intake (independent of fat type), trans &x02013; fatty acids, and alcohol intake ( Thornton et al 1983 ; Rossner and Bjor 1987 ; Lichtenstein 1999 ).

This suggests that low fat diets may adversely affect the most antiatherogenic HDL subpopulation. However, a simultaneous decrease in LDL-C with low fat diets appears to be more clinically important than the reduction in HDL-C levels. . High consumption of n-3 polyunsaturated fatty acids observed in Native Chukot Peninsula residents is associated with higher HDL-C/Apo AI ratios and increased cholesterol efflux from cellular membranes to HDL-C ( Gerasimova et al 1991 ).

Consumption of foods high in n-3 polyunsaturated fats (cold-water fish, some shellfish, as well as flax seed, canola, soybean oils and walnuts) increase HDL-C. However, the ability of n-3 polyunsaturated fats to raise HDL-C maybe influenced by TG levels. Dietary modification with omega-3 fatty acids (fish oil), such as eicosapentaenoic acid and docosahexaenoic acid, leads to significant reductions in VLDL-C (25%&x02013;30%) and triglyceride levels, yet exerts only a modest effect on HDL-C levels (0 to 3% increase) in patients with TG levels above approximately 175 mg/dL ( Kris-Etherton et al 2002 ).

This suggests that optimization of an individuals TG must occur before a clinically significant increase in HDL-C in response to a diet high in n-3 polyunsaturated fats is observed. . Moderate alcohol consumption has been shown to elevate HDL-C levels ( Ellison RC 2004 ). Mechanisms by which alcohol consumption increases HDL-C may involve changes in Apo AI synthesis and transportation, inhibition of CETP activity and stimulation of early steps in RCT ( Van der Gaag et al 2001 ).

A meta-analysis of 25 studies found that consumption of 30 g of alcohol per day increases HDL-C by about 4 mg/dl, irrespective of the type of alcohol consumed. With weighted regression, this represents a 0.133 mg/dL increase in HDL-C per gram of alcohol consumed per day, an 8% increase from pre-treatment levels ( Rimm et al 1999 ). Similarly, in a review of 340 MI patients presenting with MI, alcohol consumption was strongly associated with increased HDL-C and a significantly reduced relative risk of MI in the two highest consumption categories (&x02265;1 drink/day and 3 drinks/day) ( Gaziano et al 1993 ).

Mild to moderate alcohol consumption (1&x02013;2 alcoholic beverages several days a week) is reasonable for those individuals with low HDL-C. Caution should be used, however, when recommending alcohol consumption as a therapeutic mechanism in populations at risk for alcohol abuse. . A recent study suggests that the greatest improvement in HDL-C for both men and women in response to weight loss, exercise, and alcohol consumption was seen in individuals within the highest percentiles of HDL-C at baseline, with lower levels of baseline HDL-C being more resistant to lifestyle modifications ( Williams 2004 ).

Separating the effect of one lifestyle modification from another on HDL-C is difficult.

Introduction. HDL-.C and coronary heart disease. HDL-.C metabolism and reverse cholesterol transport (RCT). Phase one: nascent HDL-.C acquires free cholesterol. Phase two: lecithin: acyl CoA transferase (LCAT) esterifies free cholesterol. Phase three: cholesterol ester transfer protein (CETP) mediates exchange of cholesterol esters between HDL-.C and Apo B lipoproteins. Phase four: HDL-.C catabolism.

Pleiotropic effects of HDL-.C: beyond RCT. Approaches to raising HDL-.C levels: lifestyle modifictions. Approaches to raising HDL-.C levels: standard pharmacotherapy. Approaches to raising HDL-.C levels: emerging therapeutics. Summary. References. . Approaches to raising HDL-C levels: standard pharmacotherapy.. . While dietary and lifestyle modifications can raise HDL-C levels, their effect on cardiovascular outcomes may result from beneficial effects on non-HDL-C lipid components such as LDL-C.

At present, standard pharmacotherapy to raise HDL-C levels includes niacin, fibrates, and statins. .. Niacin.. Since 1955, the B-vitamin niacin (nicotinic acid) has been used in the treatment of dyslipidemia ( Altschul et al 1955 ). Niacin is the most useful pharmacologic therapy for raising HDL-C levels; it has been shown to increase HDL-C by 35%, while lowering TG levels by 20%&x02013;50% and LDL-C levels by 5%&x02013;25% ( Szapary and Rader 2004 ).

Niacin raises HDL-C levels by reducing the fractional catabolic rate of Apo AI containing HDL-C particles, decreasing hepatic removal of lipoprotein A-I (LpA-I) (a cardioprotective subfraction of HDL-C without Apo AII), and inhibiting removal of Apo AI without affecting HDL cholesterol ester ( Jin et al 1997 ); resulting in an increase of Apo AI enriched, pre-&x003b2; HDL particles ( Ganji et al 2003 ).

Using carotid intima-medial thickness (CIMT) as a measure of subclinical atherosclerosis, a randomized, placebo-controlled study of extended release niacin in addition to statin therapy in 167 patients with known CAD and low serum HDL-C (&x0003c;45 mg/dL) showed a significantly reduced rate of IMT progression in individuals without insulin resistance (p = 0.026) ( Taylor et al 2004 ). An upcoming study known as ARBITER 6-HALTS (HDL and LDL Treatment Strategies) will randomize 400 subjects with coronary heart disease to HDL-C (extended-release niacin) and LDL-C (ezetimibe) focused strategies of lipid therapy and will measure changes in mean CIMT after 14 months ( Devine et al 2007 ).

... Fibrates.. Fibric acid derivatives (fibrates) reduce CHD risk in patients with baseline LDL:HDL-C ratios of &x0003e;5.0 ( Huttunen 1991 ). Fibrates slow the progression of coronary atherosclerosis and reduce coronary events ( Ericsson et al 1996 ; Frick et al 1997 ). Fibrates induce a 5%&x02013;20% increase in HDL-C, with generally modest reductions in LDL-C and a pronounced reduction in triglyceride-rich lipoproteins ( Despres 2001 ).

. Fibrate therapy increases HDL-C levels by activating PPAR&x003b1; and by enhancing expression of Apo AI and AII, LL, and ABCA1, which collectively enhance RCT ( Tilly-Kiesi et al 1992 ). By inducing LL activity, fibrates also increase hepatic fatty acid uptake, enhance removal of LDL particles, and reduce lipid exchange between VLDL and HDL ( Staels et al 1998 ). The hypotriglyceridemic effects of fibrate therapy result from enhanced LL activity and inhibition of Apo CIII gene expression by fibrate-mediated PPAR&x003b1; activation ( Staels et al 1995 ; Motojima et al 1997 ).

. Depending on baseline lipid profiles and the potency of individual fibrates, variable effects on HDL-metabolism have been observed. Despite a greater than 15% increase in HDL-C levels with bezafibrate therapy, the Bezafibrate Infarction Prevention (BIP) failed to demonstrate a significant reduction in the primary composite end point of fatal or nonfatal MI or sudden death ( Goldbourt et al 1993 ).

In contrast, in the VA-HIT study, gemfibrozil increased HDL-C on average by 7.5% with a 2% reduction in risk correlated with every 1% increase in HDL-C (Rubenset al 2001). Similarly, in the Lopid Coronary Angiography Trial (LOCAT), gemfibrozil slowed progression of coronary atherosclerosis and the formation of bypass graft lesions. ... Statins.. Statins inhibit HMG-CoA reductase, the rate-limiting step in cholesterol biosynthesis, resulting in increased LDLr density with decreases in LDL, IDL, and VLDL particle synthesis ( Farnier 1998 ; Segrest et al 2000 ).

The mechanism of statin-induced increases in HDL-C remains incompletely understood. Some studies suggest increased HDL-C results from a decreased fractional catabolic rate of Apo AI and an increased production of Apo AI induced by inhibiting HMG-Co A reductase ( Schaefer et al 1999 ). Statins have also been shown to increase Apo AI levels by inhibiting the Rho-A kinase signal transduction pathway, resulting in activation of PPAR&x003b1; ( Martin et al 2001 ).

. Statins may also reduce hepatic lipase activity, resulting in enhanced synthesis of mature HDL-C. Another potential mechanism for increased HDL-C levels in response to statin therapy is by inhibiting CETP activity. A study of patients with the &x0201c;B1&x0201d; variant of the CETP gene showed high levels of baseline CETP activity and low levels of HDL-C with corresponding progression of atherosclerosis.

Treatment with pravastatin abolished the progression in atheromatous burden and non-significantly increased HDL-C levels in patients with the &x0201c;B1&x0201d; variant ( Kuivenhoven et al 1998 ). . Of the available statins, simvastatin, rosuvastatin, and fluvastatin more effectively raise HDL-C levels compared with atorvastatin at doses that lead to similar reductions in LDL-C. In a 36-week, multicenter, double-blind, dose titration study, 826 patients with LDL-C &x0003e;160 mg/dL and triglyceride &x0003c;350 mg/dL were randomized to receive titrated doses of simvastatin (maximum 40 mg/day) or atorvastatin (maximum 40 mg/day) over 6&x02013;12 weeks.

Significantly greater increases in HDL-C and Apo AI with simvastatin compared to atorvastatin (HDL-C: 9% vs 7% p &x0003c; 0.001; Apo AI: 6% vs 3%, p &x0003c; 0.001) were observed ( Kastelein et al 2000 ). Independent clinical studies have shown that 40 mg/day of simvastatin increase HDL-C by approximately 7%&x02013;9% versus a 4%&x02013;5% increase with 20 mg/day of atorvastatin ( Heinonen et al 1996 ; Crouse et al 1999 ).

Generally niacin is more effective than statins alone in raising HDL-C levels. ... Combination therapy.. Combination therapy using statins with niacin or fibrates has been evaluated in a number of small clinical trials ( Davidson 2002 ). The HDL Atherosclerosis Treatment Study (HATS) studied the combination of statin plus extended-release niacin in 160 patients with known CAD, low serum HDL-C levels (&x0003c;35 mg/dL in males and &x0003c;40 mg/dL in females), LDL-C levels &x0003c;145 mg/dL, and TG levels &x0003c;400 mg/dL.

Introduction. HDL-.C and coronary heart disease. HDL-.C metabolism and reverse cholesterol transport (RCT). Phase one: nascent HDL-.C acquires free cholesterol. Phase two: lecithin: acyl CoA transferase (LCAT) esterifies free cholesterol. Phase three: cholesterol ester transfer protein (CETP) mediates exchange of cholesterol esters between HDL-.C and Apo B lipoproteins. Phase four: HDL-.C catabolism.

Pleiotropic effects of HDL-.C: beyond RCT. Approaches to raising HDL-.C levels: lifestyle modifictions. Approaches to raising HDL-.C levels: standard pharmacotherapy. Approaches to raising HDL-.C levels: emerging therapeutics. Summary. References. . Approaches to raising HDL-C levels: emerging therapeutics.. . Based on preclinical data, multiple strategies to enhance the beneficial effects of HDL-C are being considered.

HDL-C delipidation therapy ( Kostner et al 2002 ), exogenous Apo AI mimetics ( Navab et al 2004 ), CETP inhibition ( Brousseau et al 2004 ), LXR/RXR agonists ( Brewer et al 2004 ), selective and non-selective PPAR agonists ( Oliver et al 2001 ; Schmitz et al 2002 ), and drugs targeting HDL-C catabolism ( Mezdour et al 1997 ; Jansen et al 2004 ) are among some of the novel emerging therapies harnessing the anti-atherogenic, anti-oxidant, anti-inflammatory, and pro-endothelial functions of HDL-C.

.. HDL-C delipidation therapy.. Selective HDL-C delipidation therapy utilizes plasmapheresis whereby extracted plasma is mixed with a delipidating agent and separated into an inorganic and organic phase. The organic component contains a high concentration of delipidated HDL, similar to lipid-poor pre-&x003b2; HDL produced by the liver, which is then returned to the circulation. In a series of animal studies delipidation therapy has been shown to markedly increase circulating pre-&x003b2; HDL levels and subsequently increase ABCA1-mediated cholesterol efflux from peripheral cells without exerting a significant effect on LDL-C metabolism Animal studies evaluating delipidation therapy followed by intravascular ultrasound assessment of vascular plaque progression or regression are ongoing ( Shah 2007 ).

... Exogenous administration of Apo AI and Apo AI mimetics.. . Exogenous administration of Apo AI directly enhances RCT via the ABCA1 pathway ( Zhang et al 2003 ; Navab et al 2004 ; Arakawa et al 2004 ). Treating normal human LDL-C with exogenous Apo AI in vitro reduces levels of oxidized lipids by 50%&x02013;60% and prevents monocyte chemotactic activity, a primary step in atherogenesis ( Poon et al 1997 ).

Exogenous administration of Apo AI-associated lecithin discs reduces the ability of LDL to induce monocyte chemotaxis, increases concentrations of pre-&x003b2; HDL, and stimulates RCT in human subjects ( Nanjee et al 2001 ). Apo AI infusions also modulate phospholipids transfer protein (PLTP), LCAT, and CETP activity, all of which potentially contribute to RCT ( Kujiraoka et al 2003 ). . Recently, Tardiff and colleagues administered 4 weekly infusions of a mixture of human wild-type Apo AI and soybean phosphatidylcholine (CSL-111; 40 mg/kg or 80 mg/kg) or volume-matched placebo to 183 patients presenting with an acute coronary syndrome as part of the Effect of reconstituted HDL on Atherosclerosis &x02013; Safety and Efficacy (ERASE) study.

Two weeks after the last infusion, intravascular ultrasound (IVUS) and quantitative coronary angiographic (QCA) measurements were compared to baseline. Patients receiving CSL-111 experienced a &x02212;3.4% change in atheroma volume (p = 0.48 vs placebo; p &x0003c; 0.001 vs baseline) with an absolute change of &x02212;5.3 mm3 (p = 0.39 vs placebo; p &x0003c; 0.001 vs baseline). Notable, transient liver function abnormalities were observed in the CSL-111 group versus placebo.

One patient developed a 100-fold increase in ALT levels in the high dose (80 mg/kg) infusion group ( Tardif et al 2007 ) While the primary endpoint of the study was negative, the data presented suggest a potential benefit for inducing plaque regression. This study highlights the complexity surrounding exogenous Apo AI therapy. . Based on observations in a family with low HDL-C and a lack of atherosclerotic disease from Limone sul Garda, Italy, a variant form of Apo AI, known as Apo AI Milano (AIM), was identified in 1980 ( Franceschini et al 1980 ).

A cysteinearginine substitution at position 173 in the amino acid sequence allows the mutant protein to form disulfide bonds with other Apo AI molecules and Apo AII. AIM homodimers and heterodimers may enhance cholesterol efflux thereby augmenting RCT ( Chiesa et al 2002 ). . Administration of recombinant Apo AI Milano (rAIM) reduces plaque cross sectional area compared to saline-placebo by up to 40% in rabbit carotid models of atherosclerosis ( Ameli et al 1994 ; Ibanez 2007 ).

Similar results have been demonstrated in balloon injured arteries in hypercholesterolemic rabbits, Apo E-deficient mice, and in transgenic mouse models of Apo AI over-expression ( Rubin et al 1991 ; Shah et al 1998 ). Exogenous HDL-C or Apo AI administration also enhance fecal steroid excretion, increase serum pre-&x003b2; HDL, and enhance RCT in humans ( Westman et al 1995 ; Eriksson et al 1999 ).

. In 2003 a landmark study using rAIM (ETC-216) quantified coronary plaque volume as a response to pharmacologic intervention with intravascular ultrasound (IVUS). This study evaluated the effect of exogenous administration of ETC-216 on coronary atherosclerosis in patients with acute coronary syndromes. ETC-216 reduced total atheroma volume by 1.3% (39.7&x02013;38.4) and 0.7% (37.2&x02013;36.6) in the moderate and high dose treatment groups respectively, while a 0.14% (34.8&x02013;34.9) increase was noted in the placebo group ( Nissen et al 2003 ).

This &x0201c;proof-of-concept&x0201d; study demonstrated the ability of Apo AI mimetic peptides to halt progression and potentially induce regression of atheromatous plaque. . A series of Apo AI mimetic peptides are currently under investigation. ETC-642 is a second generation Apo AI synthetic peptide containing three charged residues in a 22 amino-acid sequence, rendering the peptide more hydrophobic (Navab et al 2005).

Within hours of treatment with ETC-642 increased HDL-C serum levels have been observed in rabbit models. Increased CE content in HDL-C indicates concomitant LCAT activation by ETC-642. This rapid elevation of HDL-C levels suggests a possible future role for Apo AI mimetic peptides in the management of acute coronary syndromes or in the setting of ischemia-reperfusion injury ( Marchesi et al 2004 ).

. Another Apo AI mimetic peptide known as D4F reduces atherosclerosis in mouse models ( Garber et al 2001 ). Peptide D4F contains 18 amino acids in a class A amphipathic helix with polar and non-polar faces yielding high lipid affinity ( Datta et al 2001 ). D4F enhances the anti-inflammatory properties of HDL-C, reduces LDL-mediated monocyte chemotaxis, reduces macrophage migration into atheromatous plaques, and reduces atherosclerosis in Apo E KO mice alone or in combination with statin therapy.

Both oral and intraperitoneal administration of D4F significantly reduced evolving atherosclerotic lesions in vein grafts but not established atherosclerotic lesions in the aortic sinus, suggesting specific types of atherosclerotic lesions may modulate the beneficial effects of Apo AI mimetic peptides ( Li et al 2004 ). . Taking advantage of the amphipathic helical structure common to apolipoproteins, numerous Apo AI mimetic peptides are being developed.

Unique helical configuration with opposing hydrophobic and hydrophilic faces enhances interaction between lipid surfaces and apolipoproteins for the removal of membrane bound cholesterol. Some novel agents under development include: ETC-588 (large unilamellar vesicles &x02013; LUV), ETC-1001 (small molecule investigational product), helical peptides (Esperion 24218), and trimeric Apo-A (Proteopharma/Borean pharma) ( Navab et al 2006 ).

... Nuclear regulation of RCT: LXR and PPAR agonists.. . Liver X-receptors (LXR) are nuclear receptors that sense excess intracellular cholesterol ( Wang and Briggs 2004 ). Hydroxylated cholesterol stimulates LXR-mediated transcription of ABCA1, which subsequently enhances RCT from peripheral tissues ( Lund et al 2006 ). Two types of LXR receptors exist, LXR&x003b1; and LXR&x003b2;.

LXR&x003b1; has been identified in liver, intestine, macrophages and adipose tissues, while LXR&x003b2; is ubiquitously expressed similar to ABCA1 ( Lala et al 2005 ). . LXR agonists prevent development of atherosclerosis by modulating metabolic and inflammatory gene expression in rodent models. Non-selective LXR agonists increase ABCA1 synthesis with a gradual increase in HDL-C serum levels ( Lund et al 2006 ).

In a mouse LXR&x003b1; knockout model, treatment with a non-selective LXR agonist increased HDL-C by day 7 with a less significant increase in hepatic TG content ( Joseph et al 2002 ). Similarly, treating LDLr KO mice with the LXR ligand, T-0901317, reduced atherosclerotic lesion development without affecting plasma total cholesterol levels ( Terasaka et al 2003 ). Recently administration of the LXR agonist GW3965 to mice increased the rate of RCT from macrophages to feces in vivo ( Naik et al 2006 ).

. A major concern associated with LXR agonists is the development of hepatic steatosis. Since LXR agonists induce genes that stimulate lipogenesis, including the sterol response element binding protein (SREBP1-c) and fatty acid synthetase (FAS). The induction of these genes in the liver cause increased hepatic triglyceride synthesis, hypertriglyceridemia, and hepatic steatosis. Current research has focused on selective LXR modulators that may circumvent this adverse effect on hepatic function ( Miao et al 2004 ).

. First identified in rodent models of fibrate-induced hepatic peroxisome proliferation, peroxisome proliferators activated receptors (PPARs) are another family of nuclear receptors closely linked to HDL-C metabolism ( Everett et al 2000 ). Acting as synthetic ligands for PPAR&x003b1; activation, fibrates increase circulating levels of HDL-C, enhance RCT and reduce vascular inflammation and thrombogenicity ( Barbier et al 2002 ; Gervois et al 2007 ).

PPAR&x003b1; agonists enhance gene expression of SR BI, Apo AI, Apo AII, LPL, and ABCA1 ( Toth 2005 ). Statins also enhance PPAR&x003b1; activity and may enhance cholesterol efflux ( Martin et al 2001 ; Inoue et al 2002 ). . Agents for the management of Type 2 diabetes such as thiazolidinediones are known PPAR&x003b3; agonists and enhance ABCA1 mediated RCT and increase HDL-C levels in primates ( Oliver et al 2001 ).

PPAR&x003b1; and &x003b3; mediate activation of the LXR/RXR heterodimer, which in turn regulates cholesterol efflux via ABCA1 and ABCG1 activation ( Schmitz et al 2002 ). Unfortunately, the development of novel PPAR agonists to date, particularly PPAR&x003b3;and PPAR&x003b1;/&x003b3;, have been halted due to preclinical and clinical adverse effects ( Rubenstrunk et al 2007 ). ... Cholesterol exchange transfer protein (CETP) inhibition..

The complex relationship between CETP activity and atherosclerotic disease has been illustrated by several recent studies evaluating CETP inhibition therapy. In the past, antisense oligodeoxynucleotides and antibodies against CETP increased HDL-C levels and reduced aortic atherosclerotic burden in cholesterol-fed rabbits ( Sugano et al 1998 ; Rittershaus et al 2000 ).

In December 2006, this study was prematurely terminated due to an excess of deaths in the torcetrapib/atorvastatin versus atorvastatin groups (81 vs 51, respectively). The adverse outcomes of the ILLUMINATE study may have been related to off-target effects of torcetrapib, such as an increase in systolic blood pressure (limited to 1&x02013;2 mmHg) or low levels of CETP inhibition and reduced RCT ( Honey 2007 ).

Introduction. HDL-.C and coronary heart disease. HDL-.C metabolism and reverse cholesterol transport (RCT). Phase two: lecithin: acyl CoA transferase (LCAT) esterifies free cholesterol. Phase three: cholesterol ester transfer protein (CETP) mediates exchange of cholesterol esters between HDL-.C and Apo B lipoproteins. Phase four: HDL-.C catabolism. Pleiotropic effects of HDL-.C: beyond RCT.

Approaches to raising HDL-.C levels: lifestyle modifictions. Approaches to raising HDL-.C levels: standard pharmacotherapy. Approaches to raising HDL-.C levels: emerging therapeutics. Summary. References. . Summary.. . A considerable body of evidence supports the correlation between HDL-C levels and cardiovascular risk. However, trials evaluating HDL-C targeted therapies are limited, in part due to a lack of pharmacologic agents specifically designed to raise HDL-C and our limited ability to measure HDL-C effectiveness.

As a result, there is not enough data to support guidelines recommending aggressive increases in HDL-C levels. With this in mind, evaluating the clinical efficacy of emerging HDL-C targeted therapies will be of paramount importance. . Given the complexity of HDL-C metabolism, serum levels of HDL-C may not be an adequate indicator of efficacy. At present, plasma HDL-C measurements have a &x000b1; 10% margin of error, which could lead to errors in measurement of up to 4 mg/dL ( Friedewald et al 2007 ).

The functional properties of circulating HDL-C levels, the kinetics of HDL-C metabolism, and the variable effects of HDL-C subfractions on atherogenesis are ignored by current laboratory measures of HDL-C ( Forrester et al 2005 ).

Introduction. HDL-.C and coronary heart disease. HDL-.C metabolism and reverse cholesterol transport (RCT). Phase one: nascent HDL-.C acquires free cholesterol. Phase two: lecithin: acyl CoA transferase (LCAT) esterifies free cholesterol. Phase three: cholesterol ester transfer protein (CETP) mediates exchange of cholesterol esters between HDL-.C and Apo B lipoproteins. Phase four: HDL-.C catabolism.

Pleiotropic effects of HDL-.C: beyond RCT. Approaches to raising HDL-.C levels: lifestyle modifictions. Approaches to raising HDL-.C levels: standard pharmacotherapy. Approaches to raising HDL-.C levels: emerging therapeutics. Summary. References. . References.. Altschul R, Hoffer A, Stephen JD. Influence of Nicotinic Acid on Serum Cholesterol in Man.

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Proteins.

Protein.

Human Genome.