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.     

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 triglyceride content in the high-density lipoproteins of patients with ischemic heart disease]

The sera and high density lipoprotein (HDL) fraction obtained from donors and patients with coronary heart disease, Functional Class II exercise-induced angina or postinfarction cardiosclerosis were studied for levels of triglycerides (TG) and cholesterol (C) and calculated for percentage of HDL cholesterol of total serum cholesterol, C/TG and HDL C/HDL TG ratios. A TG-enriched HDL fraction was detected, which had an unusual structure. Calculation of the percentage of HDL C of serum total cholesterol levels much more revealed lower concentrations of HDL C.     

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.     

Modulation of high-density lipoproteins in a population in istanbul, Turkey, with low levels of high-density lipoproteins

The extent to which high-density lipoprotein (HDL) cholesterol levels can be increased in patients with low HDL cholesterol is important because low HDL cholesterol levels increase the risk of coronary heart disease (CHD). During the past 14 years, we have assessed risk factors in Turks, a population in which extremely low HDL cholesterol levels (mean 36 mg/dl in men, 42 mg/dl in women) are a prime CHD risk factor. Although genetically determined to a significant extent, these low HDL cholesterol levels can be modulated by lifestyle factors, as in other populations. We measured the HDL cholesterol levels in men and women residing in Istanbul at 3 time points: 1990 to 1993, 1996 to 2000, and 2003. The mean HDL cholesterol levels increased from 45.3 +/- 9.5 mg/dl in 1990 to 1993 to 49.7 +/- 12 mg/dl in 2003 (p <0.0001) in women, but were virtually unchanged in men (38 +/- 8 vs 39 +/- 10 mg/dl). In contrast to previous years, the HDL cholesterol levels in women in 2003 were markedly affected by education level and socioeconomic status, averaging 56 +/- 9 mg/dl in those with a university education and 48 +/- 12 mg/dl in those with a primary school education. Part of this difference could be explained by less smoking and more exercise and lower body mass index (average 25.6 +/- 4.9 vs 29.7 +/- 5.1 kg/m(2)) of the highly educated women. It is important to note the increase in the prevalence of obesity between the 1990 to 1993 interval and 2003 in men and women, including a remarkable change from 9.4% to 45.2% among women with a primary school education. None of these factors affected the HDL cholesterol levels of men by >2 mg/dl at any of the 3 points. In conclusion, because CHD risk changes by as much as 2% to 4% per 1 mg/dl difference in HDL cholesterol level, the 8 mg/dl difference may reflect as much as a 20% to 30% reduction in CHD risk associated with the benefit of higher education in women. Why education failed to affect the HDL cholesterol levels in Turkish men remains unclear.     

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.     

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.     

Prognostic value of exercise angioscintigraphy in coronary disease]

Multivariate survival analysis (MSA) was applied to 97 patients with coronary disease using the Cox model and a stepwise regression procedure. Seventeen variables including data based upon clinical examination, exercise testing (ET), and exercise angioscintigraphy (EAS) as well as coronary arteriography were studied in each patient. During the monitoring period (interval: 1-57 months), 38 patients sustained a cardiac event (recurrence of coronary disease or death). Neither resting left ventricular ejection fraction, nor coronary anatomy were significant prognostic variables. The only two variables identified by MSA were a variable of EAS: corrected ejection fraction at maximum exercise (p less than 0.008), and a variable of ET: maximum heart rate during exercise (p less than 0.03). This study shows that the prognosis of a coronary disease patient can best be assessed by two variables which are both exercise parameters.     

The effects of statins on high-density lipoproteins

Statins inhibit cholesterol synthesis and are effective in lowering total cholesterol levels in plasma or serum due to reductions in low-density lipoprotein and very low-density lipoproteins, as well as reducing progression of coronary atherosclerosis, coronary heart disease, and stroke morbidity and mortality. These agents also modestly raise levels of high-density lipoprotein (HDL) cholesterol and its major protein, apolipoprotein (apo) A-I. The more effective statins can also raise the levels of large α-I HDL particles as assessed by two-dimensional gel electrophoresis. High levels of these particles promote reverse cholesterol transport and protect against coronary heart disease and progression of coronary atherosclerosis. The mechanism whereby statins alter HDL and its subspecies appears to be due to reduction of triglyceride-rich lipoproteins, with a secondary decrease in cholesteryl ester transfer protein activity, and less transfer of HDL cholesterol to triglyceride-rich lipoprotein acceptor particles. Increasingly, statins will be combined with other agents such as ezetimibe, fibrates, niacin, and cholesteryl ester transfer protein inhibitors to optimize the entire lipoprotein profile to alter not only low-density lipoprotein, but also HDL, triglycerides, lipoprotein(a), and C-reactive protein, and also to reduce cardiovascular morbidity and mortality.     

Immunolocalization of high-density lipoproteins in arterial walls of rats

The inverse correlation between serum high-density lipoprotein (HDL) levels and coronary heart disease in humans suggests that HDL has a protective effect against the development of atherosclerosis. However, there is a lack of data concerning its distribution across the arterial wall. In order to detect this lipoprotein, we performed immunogold labeling on ultrathin sections of L.R. White embedded rat arterial tissue. Electron microscopic examination revealed that HDL was localized in the cytoplasm of the endothelial cells and the smooth muscle cells, but not in the nucleus or other organelles. The HDL was also present in the subendothelial space, the extracellular matrix as well as the intercellular clefts between the endothelial cells. Quantitative study revealed that rats on a high cholesterol diet for one month have more immunogold labeling (P < 0.05) in the subendothelial space, the smooth muscle cells and the extracellular matrix as compared to rats on a normal diet. After 12 months of normal diet, the intracellular labeling was significantly increased (P < 0.05) in the endothelial cells and the smooth muscle cells as compared to 1 month on the normal diet. The increase was greater (P < 0.05) for the high-cholesterol diet than for the normal diet treatment.     

Relation of high-density lipoproteins to coronary artery disease

Low mean concentrations of high-density lipoprotein (HDL) cholesterol have long been recognized as a characteristic of patients with coronary heart disease, and the measurement of this fraction is a relatively strong discriminator between patients with coronary heart disease and those without. When subjects are ranked by the severity of coronary atherosclerosis determined angiographically, levels of HDL cholesterol, particularly of its HDL₂ subclass, are consistently lower in subjects with extensive disease than in those with minimal atheroma. HDL cholesterol is derived from a number of sources, mobilization from peripheral tissues being but one. Generally, longitudinal studies have confirmed that a low HDL cholesterol level is potently and independently predictive of a high risk of coronary heart disease, one exception being a study of subjects with hypercholesterolemia. Despite the strength of these epidemiologic associations, there is no evidence from experimental studies or clinical trials to establish that low HDL levels are causally important in atherogenesis.     

Changes in the distribution and composition of high-density lipoproteins in primary hypothyroidism

The distribution and composition of high-density lipoprotein (HDL) subclasses were investigated in 14 women with severe hypothyroidism who were studied before and during treatment. The plasma concentrations of triglycerides, total cholesterol, HDL cholesterol, and of the apoproteins (apo) A-I, B, and E were increased in the hypothyroid state, while the apo A-II levels did not change significantly. After normalization of the thyroid function tests, the lipid and apoprotein levels were similar to those of normal individuals. Isopycnic ultracentrifugation in the density range 1.020 to 1.210 g/mL showed increases of both cholesterol and apo B in very-low-density lipoprotein (VLDL) and in low-density lipoprotein (LDL). The distribution of the HDL subclasses was modified in the hypothyroid subjects; both the less dense HDL fraction (d 1.063 to 1.100 g/mL; HDL2b), and the denser subclass (d 1.150 to 1.210 g/mL; HDL3b+3c) were increased, while the intermediate density subfraction (d 1.100 to 1.150 g/mL; HDL2a+3a) did not vary significantly. This redistribution of the HDL subfractions was associated with increased concentrations of cholesterol, phospholipid, and apo A-I in HDL2b, and of phospholipid and apo A-I in HDL3b+3c. Treatment of hypothyroidism decreased the concentrations of these fractions, and HDL2a+3a became the major HDL subclass in the euthyroid state. The particle sizes within HDL subfractions, measured by polyacrylamide gradient gel electrophoresis, were identical in the untreated and treated patients. The increased mass of protein and lipid within HDL2b and HDL3b+3c could therefore be attributed to an accumulation of identical-sized particles. The overall lipid and protein composition of the HDL lipoproteins was similar before and during treatment.(ABSTRACT TRUNCATED AT 250 WORDS)     

Hypertension, changes in high-density lipoproteins and antihypertensive therapy

The risk for development of coronary heart disease (CHD) is related to a number of factors. Among these, both hypertension and various lipid abnormalities have been shown to play an important role. A clear inverse relation between high-density lipoprotein (HDL) cholesterol and CHD has been observed in numerous observational and short studies. Pharmacologic treatment of hypertension has been shown to reduce dramatically some of the sequelae of high blood pressure--renal failure, cerebrovascular accidents and congestive heart failure. However, a consistent reduction in associated CHD has not been demonstrated, and the dissociation between reducing blood pressure and reduction in CHD has not been definitively explained. One of the suggested explanations relates to alterations in blood lipid levels that may be induced by certain antihypertensive agents. Changes in HDL cholesterol levels or other lipid alterations due to antihypertensive therapy could modify the beneficial effects achieved by the direct reduction of blood pressure. If so, antihypertensive agents could be subclassified as atherogenic or antiatherogenic depending on the associated changes in lipid levels. Therefore, the antihypertensive agents of choice for patients whose cholesterol levels are a concern would be those that reduce the CHD risk factor of hypertension without compromising the risk factor associated with a patient's lipid profile.