The metabolism of high-density lipoproteins

Although high-density lipoproteins (HDLs) have been shown to be the best single indicator of the risk of coronary heart disease (CHD), relatively little is known about their metabolism. Accordingly, only limited strategies are available for therapeutically raising plasma HDL levels. The circulating HDL particle is assembled in the blood as the result of remodeling the nascent discoidal HDL followed by transfer of lipid and protein components from other lipoproteins. The catabolism of HDL is equally complex. The receptor-mediated removal mechanism of HDL from the plasma has yet to be substantiated. Despite the extensive studies performed, no clear mechanism has emerged whereby HDL particles protect the arteries from atherosclerosis. Reverse cholesterol transport remains an attractive hypothesis, but several other potential mechanisms may also play a role in the interaction between HDL and the arterial surface. Recent studies related to the regulation of HDL metabolism are discussed with particular emphasis on the potential role of the postprandial state. A brief discussion is also provided on potential future strategies for regulating HDL levels through pharmacologic intervention.     

Genetics of high-density lipoproteins

PURPOSE OF REVIEW: High-density lipoproteins have multi-factorial anti-atherosclerosis properties: they have potent anti-oxidant effects and prevent the oxidation of low-density lipoproteins; they have anti-inflammatory effects; they modulate vascular endothelial cell function and transport cholesterol back to the liver for excretion into the bile - a process called reverse cholesterol transport. The present review focuses on genetic aspects of high-density lipoprotein metabolism, with genomic approaches used to identify genes that regulate high-density lipoproteins in humans. RECENT FINDINGS: Disorders of the many genes that code for proteins, including transporters, enzymes, receptors, transfer proteins and lipases, involved in high-density lipoprotein metabolism have been identified in humans as causing extremes of high-density lipoprotein cholesterol, and provide potential novel therapeutic avenues. These, however, explain fewer than 5% of the causes of low high-density lipoprotein cholesterol in the general population. SUMMARY: Genome-wide linkage studies of large cohorts, with discrete as well as quantitative trait loci analyses, followed by association studies have enabled the identification of large chromosomal regions that may harbor genes that modulate high-density lipoprotein cholesterol levels in humans. Using mouse genetics, the results of the HapMap project and novel genetic approaches will allow the discovery of novel genes in high-density lipoprotein metabolism.     

Influence of exercise on high-density lipoproteins

The effects of an intensive rehabilitation course on plasma high-density lipoprotein (HDL) levels were studied in 40 men, aged 29 to 56 years, with ischemic heart disease. The exercise consisted of aerobic activities that induced up to 80% of the maximal heart rate during three 20-minute periods daily for 5 days a week; the program lasted 3 weeks. Significant increases were found in the levels of HDL and HDL₂ and their ratios to total plasma cholesterol. These changes were similar in nonsmokers of cigarettes and in men who gave up or reduced smoking during the course and contrasted with negligible changes in those who continued to smoke.     

Influence of diet on high-density lipoproteins

Evidence of a relation between diet and high-density lipoprotein (HDL) levels in humans comes from numerous cross-sectional and experimental studies. Evaluation of data from cross-sectional nutrition and health surveys sometimes yields different results for men and women but usually demonstrates positive correlations of HDL cholesterol levels with total energy intake, alcohol consumption, dietary cholesterol and total and animal fat, and negative correlations of HDL with dietary carbohydrates (simple sugars) and, in some instances, plant fats. Short-term dietary manipulation produced confirmatory evidence of a causal relation between diet and HDL with regard to several of these factors; however, there are few long-term data. The underlying mechanisms as well as the relation of HDL manipulation to cardiovascular health are still to be defined, particularly because the functions and fates of the HDL molecule may vary according to its composition and turnover, which are not reflected by the HDL cholesterol concentration. Furthermore, some relations between diet and HDL may only be the result of other metabolic consequences of dietary change, for instance, triglyceride metabolism and other lipoproteins. Although there is consistent evidence that a high HDL cholesterol level is indicative of a low risk of coronary heart disease in industrialized populations, evidence is inconclusive that manipulation of HDL leads to an alteration of risk.     

Influence of gemfibrozil on high-density lipoproteins

In animal studies, gemfibrozil markedly elevates high-density lipoprotein (HDL) cholesterol levels, In humans with primary hyperlipoproteinemia and lipoprotein phenotypes IIA, IIB and IV, gemfibrozil, 1,200 mg/day, was associated with a 25%, 20% and 17% increase in HDL cholesterol, respectively. Gemfibrozil also substantially increased the ratio of HDL to total cholesterol, reflecting both an increase in HDL cholesterol and a decrease in very low density lipoprotein cholesterol and low-density lipoprotein cholesterol. Compared with a placebo in subjects with types IIA, IIB and IV lipoprotein phenotypes, therapy with gemfibrozil led to an increase of 33%, 34% and 23%, respectively, in the ratio of HDL cholesterol to total cholesterol. With gemfibrozil therapy, about 80% of subjects with hypertriglyceridemia had a reduction in triglycerides of 35 % or a return to normal levels; 50 % of subjects with hypercholesterolemia had a cholesterol reduction of 20% or a return to normal levels.     

Interrelationship of triglycerides with lipoproteins and high-density lipoproteins

Triglycerides are transported by the largest and most lipid-rich of the lipoprotein particles, namely, chylomicrons and very low density lipoproteins (VLDL). These particles are buoyant because of the high triglyceride content, which makes up approximately 90% by weight of the chylomicron and 70% by weight of the VLDL. The chylomicron transports exogenous or dietary fat and cholesterol, whereas VLDL transports endogenous triglyceride and cholesterol in lipoproteins synthesized and secreted by the liver. Both chylomicrons and VLDL are hydrolyzed at the capillary surface by the enzyme lipoprotein lipase. Lipoprotein lipase catalyzes the hydrolysis of triglyceride in the lipid core of these particles, producing smaller particles known as remnants. We currently believe the remnants are atherogenic and that this is one reason why hypertriglyceridemia may predispose to coronary artery disease. Chylomicron remnants are recognized and removed by hepatic receptors that contain apolipoprotein (apo) E. The rate of clearance of remnant particles depends on which subfraction of apo E is present. Particles containing apo EII are removed more slowly than those with apo EIII and EIV. The dietary cholesterol from the chylomicron remnant particles is thought to down-regulate the hepatic low-density lipoprotein (LDL) receptors. VLDL remnants, also called intermediate-density lipoprotein (IDL), contain apo E and may be removed by the liver through the LDL or B/E receptor. The decrease in activity of these receptors results in apparent oversynthesis of LDL, the end-product of VLDL and IDL metabolism. LDL is the major cholesterol carrier, followed by high-density lipoprotein (HDL).(ABSTRACT TRUNCATED AT 250 WORDS)     

The protective role of high-density lipoproteins in atherosclerosis

Serum high-density lipoprotein level is known to be correlated inversely with the incidence and mortality rates of ischemic heart disease. Although some reports pointed out that in case of hyperalphalipoproteinemia, lesions in the coronary arteries were occasionally found, it is also noticed that in very rare condition, no atheromatous lesions found even in patients with hereditary alphalipoprotein deficiency (Funke et al., 1991). However, clinical surveys have confirmed that high high-density-lipoprotein cholesterol level is favorable in preventing the development of atheroclerotic lesion and high-density lipoprotein together with apolipoprotein AI are currently considered to be the most reliable parameters in predicting the development of atherosclerosis in hyperlipidemia.     

The pleiotropic effects of statins

PURPOSE OF REVIEW: 3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) are the most widely prescribed drugs worldwide for lowering cholesterol levels. In use for more than 15 years, they have demonstrated efficacy, safety, and tolerability across a broad range of patients. This class of drugs has been designed to lower the cholesterol level by competitively inhibiting the enzyme responsible for its biosynthesis and thereby to play a major role in reducing cardiovascular risk. However, both basic evidence and clinical evidence also supports the idea that reductions in cardiovascular risk are dependent on mechanisms beyond cholesterol reduction alone, such as the reduction of endothelial dysfunction, inhibition of inflammatory responses, stabilization of atherosclerotic plaques, and modulation of procoagulant activity and platelet function. RECENT FINDINGS: In fact, as shown in several clinical trials, the beneficial effects of statin treatment begin earlier than its cholesterol-lowering effect. These other mechanisms could act in concert with the potent low-density lipoprotein cholesterol-lowering effects of this class of drugs to exert early and lasting cardiovascular protective effects. Recently, several studies have shown that an intensive lipid-lowering regimen with a statin provides greater protection against death or major cardiovascular events than does a standard regimen. SUMMARY: This review summarizes the new findings in these pleiotropic effects and describes their impact on vascular processes.     

The cardioprotective effects of statins

Many large randomized clinical trials have demonstrated that statins are effective in terms of prevention of cardiovascular events. It has been presumed that these beneficial effects could be due to not only improved plasma lipid profiles but also to the direct actions on the vascular wall. In addition to the direct vascular protective effects, several lines of experimental evidence have been accumulated that statins have also cardioprotective effects against ischaemia/reperfusion injury. This effect appears to be a class-effect and activation and up-regulation of eNOS by statins play an important role.     

The cardioprotective effects of statins

In addition to their lipid-modulating properties, statins have a large number of beneficial cardiovascular effects that have emerged over time and that were not anticipated during drug development. The lipid and nonlipid effects act in a concerted way to reduce the ischemic burden of the myocardium and to protect it against injury. By acting on the vessel wall, statins may prevent lesion initiation and repair injuries, enhance myocardial perfusion, slow lesion progression, and prevent coronary occlusion. They may also directly reduce myocardial damage, favor myocardial repair, and protect against immune injury. This review focuses on properties of statins that contribute to their cardioprotective effect. The first section includes information on modulation of vascular tone, endothelial permeability and function, inhibition of complement injury, curbing of foam cell formation, antioxidant and anti-inflammatory properties, and profibrinolytic and anticoagulant activities. The second section relates to reduction of myocardial necrosis, myocardial hypertrophy, blood pressure, and heart failure, as well as mobilization of endothelial progenitor cells for repair, angiogenic effects, and immunomodulation. In many instances, results of in vitro and animal studies have raised expectations and prompted studies in humans. Several clinical trials have confirmed these expectations and have strengthened the value of statins as valuable antiatherosclerotic and cardioprotective agents.     

The antioxidant effects of statins

Oxidative stress contributes to the initiation and the development of atherosclerotic plaques and adversely influences myocardial integrity. Statins interfere with oxidation in several ways that may contribute to reducing the atherogenic process. In addition to direct antioxidant effects, statins reduce circulating oxidized low-density lipoproteins (oxLDL) and inhibit their uptake by macrophages. They also reduce circulating markers of oxidation such as F2-isoprostane and nitrotyrosine. Statins inhibit oxidant enzymes activity such as that of reduced nicotinamide adenine dinucleotide phosphate (NAD[P]H) oxidase and myeloperoxidase and up-regulate the activity of antioxidant enzymes such as catalase and paraoxonase. They reduce endothelial dysfunction mainly by their ability to enhance endothelial nitric oxide bioavailability, which is achieved by several mechanisms. The antioxidant properties of statins extend to organ protection especially the myocardium and the lungs.     

Metabolic abnormalities: high-density lipoproteins.

The dyslipidemia typically found in subjects with the metabolic syndrome includes an elevated concentration of plasma triglyceride,a low-density lipoprotein fraction in which the particles are smaller and denser than normal, and a low concentration of highdensity lipoprotein (HDL) cholesterol. This article is concerned with the low HDL component. It provides an overview of HDL structure and metabolism and describes the functions of HDLs that may be cardioprotective. The article then outlines what is known about the concentration and subpopulation distribution of HDLs in the metabolic syndrome. Possible mechanisms responsible for the low HDL are discussed. The consequences of a low HDL concentration in this syndrome are addressed before the article concludes with a discussion of whether low HDL in the metabolic syndrome should be a therapeutic target.     

Immunomodulatory role of high-density lipoproteins: impact on immunosenescence

Natural aging is accompanied by a dysregulation of the host immune response that has well-known clinical consequences but poorly defined underlying causes. It has previously been reported that advancing age is associated with an increase in membrane cholesterol level in T cells. The aim of this study was to investigate whether high-density lipoprotein (HDL) can modulate the age-related accumulation of membrane cholesterol in T cells and impact on their subsequent responsiveness. Our data reveal that cholesterol metabolism, influx, and efflux are altered in T cells with aging, which may in part explain the increase in membrane cholesterol level observed in T cells in elderly individuals. HDL was unable to promote reverse cholesterol transport in T cells from elderly subjects with the same efficiency as was observed in T cells from young subjects besides unchanged ABCA-1 and SR-BI expressions. HDL exhibited a short-acting co-stimulatory effect by enhancing T cell production of interleukin-2 (IL-2). Moreover, HDL from healthy normolipemic individuals exerted differential effects on T cell proliferation that depended on the age of the HDL donor. Finally, HDL modulated TCR/CD28 activation by inducing sustained signaling through pLck, pERK, and pAkt. These data suggest that HDL has immunomodulatory effects on T cells that are influenced by age.