High density lipoprotein (HDL) subfractions in cardiovascular patients with low levels of HDL-cholesterol. Influence of hypertriglyceridaemia on subfraction concentration and composition

The major high density lipoprotein (HDL) subfractions were examined in angiographically defined cardiovascular patients with low HDL-cholesterol (HDL-C) levels. The aims were to study subfraction concentration and composition, and the extent to which hypertriglyceridaemia (HTG) modified these variables. Normotriglyceridaemic (NTG)-low HDL-C patients showed similar subfraction composition to age-matched healthy controls. However, these groups showed notable differences in subfraction composition compared to HTG-low HDL-C patients, particularly with regard to the HDL2 subfraction. HDL subfraction mass was significantly reduced in both cardiovascular groups; the HTG group showed a greater reduction in HDL2, whilst the NTG group showed a greater reduction in HDL3. The major HDL apoprotein (apo A-I) was lower in both subfractions of the cardiovascular patients. Apo A-II showed significant reductions only in the HTG patients.     

Unique character and metabolism of high density lipoprotein (HDL) in fetus

Lipid and lipoprotein profiles, and enzymes for the lipid metabolism were compared between cord and adult blood. Consistent with previous reports, the major lipoprotein in cord blood was high-density lipoprotein (HDL), and that in adult blood was low-density lipoprotein (LDL). The level of apolipoprotein E (apo E) in cord blood was almost equivalent to that in adult blood, while other apolipoproteins and lipids were all lower than the adult level. In cord blood, apo E-rich HDL cholesterol represented more than 30% of total HDL cholesterol (around 11% in adult), and the concentration was about twice of that in adult blood. This apo E-rich HDL cholesterol was poorly esterified (E/T 56%) compared with that in adults (93%). The lecithin:cholesterol acyltransferase (LCAT) activity in cord blood was extremely low, while the activity and mass of cholesteryl ester transfer protein (CETP) were higher than those in adult blood. The apo E genotype did not show influences on total cholesterol, LDL cholesterol, total HDL cholesterol, and apo E rich HDL cholesterol levels in cord blood, as opposed to those in adult blood. The association of D442G mutation of the CETP gene with the increased HDL cholesterol in adult blood was not seen in cord blood. Rather, the mutation was associated with low total cholesterol and LDL cholesterol levels in cord blood. These results indicate that, in fetus, the character and metabolism of HDL, especially of apo E-rich HDL cholesterol, are distinct from those in adults.     

Thyroxine binding to the apolipoproteins of high density lipoproteins HDL2 and HDL3.

Four preparations of high density lipoprotein HDL2, five of HDL3, and purified apolipoproteins apoA-I, apoA-IV, and apoE were photoaffinity labeled with [125I]T4 and analyzed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Gels were also immunoblotted with antiserum against apoA-I, apoA-II, apoA-IV, apoE, or apo(a), and the immunostained membrane was then autoradiographed. In HDL2, the two major radioactive bands migrated near the origin of the resolving gel and at 28-31 kilodaltons (kDa). The first band, stained by anti-apo(a) and anti-apoB-100, accounted for 40-96% of the total radioactivity and was attributed to lipoprotein(a), which is isolated in the same density range as HDL2. The second band, stained by anti-apoA-I, accounted for 1-57% [41-95% after correction for contaminating lipoprotein(a)] of the [125I]T4 in the resolving gel. In HDL3, the major radioactive band was identified as apoA-I and contained 93-94% of the [125I]T4 in the resolving gel. Minor radioactive bands in both HDL2 and HDL3 were identified as apoA-II (17-18 kDa), apoA-II monomer (7-10 kDa), apoE (36-38 kDa), and apoAII-apoE heterodimer (46 kDa). In addition, HDL3 contained apoA-IV (43 kDa). Photoaffinity labeling of isolated apoA-IV and apoE showed that each protein interacted with [125I]T4. In both HDL2 and HDL3, photoaffinity labeling in the presence of unlabeled L-T4 (1-10 microM) showed inhibition, suggesting a Kd in the micromolar range. This inhibition varied among different apo bands of the same HDL2 or HDL3 preparation and among the same bands of different preparations. Labeling in the presence of heparin or other inhibitors of T4 binding to plasma proteins (furosemide, diclofenac, and mefenamic acid) showed that HDL2-associated apoA-I was more sensitive to inhibition than HDL3-associated apoA-I. In conclusion, 1) HDL2 and HDL3 carry T4 mainly through apoA-I and secondarily through apoA-II and apoE. The inter- and intrasubclass variations in T4 binding and sensitivity to inhibitors can be explained by the known heterogeneity of HDL particles and possible differences in conformation of the apo. The findings reported here, that apo other than apoA-I and apoB exhibit saturable binding of T4, suggest that thyroid hormone-lipoprotein interactions may have even wider physiological implications than previously appreciated.     

The metabolic fate of high density lipoprotein (HDL) in the diabetic rat

Summary Diabetic rats, pre-fed and maintained on a sucrose-rich diet, have marked hyperlipoproteinaemia, with an increase in both very low density (VLDL) and high density lipoproteins (HDL). HDL obtained from both diabetic and non-diabetic rats and labelled with ¹²⁵I or ¹³¹I was injected simultaneously into diabetic and non-diabetic rats. The half life of the two HDL preparations was similar in both diabetic and non-diabetic rats and ranged between 11.4 to 12.0 hours. A-I apolipoprotein had a disappearance rate parallel to the whole HDL, in contrast to the apo-C peptides which had a faster rate of removal. Although the fractional catabolic rate (FCR) of HDL preparations was slower in the diabetic rats, there was a 16% increase in the calculated synthetic rate (SR) of HDL-protein. These observations could explain the increased plasma HDL levels in the sucrose-fed, streptozotocin-induced diabetic rat.This work was presented in part at the 12th Annual Meeting of the European Association for the Study of Diabetes (EASD), Helsinki, Finland, September 1976     

Changes of serum lipids and high density lipoprotein levels in patients with bronchial asthma

Serum lipid levels of 60 cases of bronchial asthma (males 30, females 30) were compared with 161 (males 91, females 70) controls. Serum cholesterol, triglyceride, Apo A1, A2, B, HDL-cholesterol (HDL-C), LDL VLDL, and atherosclerotic index (T-chol. HDL-chol/T-chol.) were measured. Asthma cases slowed low levels of serum cholesterol, triglyceride, LDL, VLDL and Apo B compared to the control group, while HDL-C, ApoA2 were higher than the control group. (p less than 0.05). The atherosclerotic index was low in the asthma group. A patient who had a 9-year history of asthma showed decreased HDL-C and increased T-cholesterol, on improvement of asthma attack and body weight loss.     

Seasonal variation of serum high density lipoprotein cholesterol levels in men

To determine if there are seasonal variations in serum high density lipoprotein cholesterol (HDL-C), the concentration of HDL-C was measured monthly for 12 consecutive months in 31 healthy men and 24 male inpatients with schizophrenia. In addition to HDL-C, total cholesterol (TC) and triglyceride (TG) concentrations in serum were assayed, and low density lipoprotein cholesterol (LDL-C) was estimated by calculation. Mean serum HDL-C levels of schizophrenic patients were significantly low compared with those of healthy controls, 35 +/- 12 and 49 +/- 11 mg/dl, respectively. The TC levels of schizophrenic patients were significantly higher in January and March as compared with August. The HDL-C levels in summer and autumn were significantly lower than those in winter and spring in both healthy men and schizophrenic patients. The concentration of LDL-C was significantly high in September and October as compared with April in healthy men. In patients with schizophrenia, LDL-C level seemed higher in January and March as compared with August.     

Effects of nicotinic acid on serum cholesterol concentrations of high density lipoprotein subfractions HDL2 and HDL3 in hyperlipoproteinaemia

Nicotinic acid was given in a 4-g daily dose for 6 weeks to 41 weight-stable patients of mean age (+/- SD) 52 +/- 9 years, with type IIa, type IIb or type IV hyperlipoproteinaemia (HLP), in order to study its effects on serum cholesterol concentrations of high density lipoprotein (HDL) subfractions HDL2 and HDL3. The triglyceride and cholesterol levels of serum very low density (VLDL) and low density (LDL) lipoproteins decreased during treatment (P less than 0.001). Serum HDL and HDL2 cholesterol levels increased by 37% and 135%, respectively. These changes were positively correlated (r = 0.93; P less than 0.001). There was no significant change in mean serum HDL3 cholesterol concentration. A negative correlation existed between changes in HDL3 and HDL2 cholesterol levels (r = -0.54; P less than 0.001). Multiple stepwise linear regression analyses revealed that the initial HDL3 cholesterol predicted more than 30% of the increase in HDL2 cholesterol. Changes in the concentrations of HDL2 and HDL3 cholesterol after 6 weeks of drug treatment were not related to the type of HLP, neither were these effects of nicotinic acid correlated with changes in VLDL or LDL lipid levels. The concept has previously been proposed, on the basis of in vitro data, that HDL2 is formed from HDL3 particles in the blood. Our results suggest that, in man, this reaction is stimulated in vivo by prolonged nicotinic acid therapy.     

The inheritance of high density lipoprotein cholesterol and apolipoproteins A-I and A-II

The surface sialic acid content of aortic endothelial cells in vitro was substantially lower in sparse cultures than at confluence. Binding of LDL to endothelial cells did not change at different culture densities and was unaffected by brief pretreatment with neuraminidase to partially remove surface sialic acid residues. In contrast, internalization of LDL declined by a factor of 3 between low density cell cultures and confluent monolayers; neuraminidase pretreatment increased LDL uptake and the effect was most marked (greater than 10-fold) at confluence. Pretreatment with cationised ferritin, which removed most of the surface sialic acid residues as well as glycosaminoglycans, increased LDL internalization by up to 20-fold, again with most effect on confluent monolayers. Thus LDL uptake is inversely correlated with sialic acid content. We conclude that changes in the surface density of sialic acid (and possibly other charged) residues significantly modulate endothelial LDL uptake, and suggest that focal increases in LDL accumulation during atherogenesis may be related to alterations in endothelial endocytic properties at sites of increased cell turnover or damage.     

High-density lipoprotein (HDL) from elderly and reconstituted HDL containing glycated apolipoproteins A-I share proatherosclerotic and prosenescent properties with increased cholesterol influx

High-density lipoprotein (HDL) is a strong antioxidant, anti-inflammatory, and antisenescence molecule. However, in the current study, HDL from the elderly group (E-HDL) exhibited increased glycation with apolipoprotein (apo) A-I multimerization and decreased phospholipid content. Similarly, glycated apoA-I (gA-I) by fructosylation has a covalently multimerized band without a crosslinker and impaired phospholipid-binding ability. Treatment of human dermal fibroblasts and macrophages with E-HDL and gA-I caused more severe cellular senescence and foam cell formation, respectively; however, treatment with HDL from a young group (Y-HDL) and native apoA-I (nA-I) suppressed senescence and atherosclerosis. E-HDL(3) and reconstituted HDL (rHDL) containing gA-I showed enhanced cholesterol influx into macrophages compared with Y-HDL(3) and nA-I-rHDL. In conclusion, E-HDL and gA-I-rHDL share similar physiologic properties in macrophages and human dermal fibroblasts. E-HDL and gA-I-rHDL exacerbated cellular senescence and atherosclerosis with increased cellular cholesterol influx.     

A low high density lipoprotein (HDL) level is associated with carotid artery intima-media thickness in asymptomatic members of low HDL families

Low serum high-density lipoprotein cholesterol (HDL-C) is a strong predictor of coronary heart disease (CHD). The aim of the present study was to evaluate the metabolic parameters predicting the atherosclerotic changes in asymptomatic members of low HDL-C families. We performed carotid B-mode ultrasonography with intima-media thickness (IMT) measurement for 89 asymptomatic members of Finnish low HDL-C families. The family members were categorized as affected or unaffected according to the 10th age-gender specific HDL-C percentile. In the affected group, the most marked decrease of HDL subclasses was observed for HDL2-C when compared with the unaffected (109% difference). In the partial correlation analyses, age and gender showed significant correlations with the mean IMT (for age, r=0.880, P<0.001, and for gender, r=-0.361, P=0.018). Importantly, HDL-C and HDL2-C were significantly inversely related to the mean carotid IMT, also after correction for age (for HDL-C, r=-0.186, P=0.043, for HDL2-C, r=-0.208, P=0.029, when adjusted for age). The correlation for HDL-C was significant also when adjusted for gender. In conclusion, low HDL-C is associated with increased carotid artery IMT in asymptomatic members of low HDL-C families.     

脂蛋白(a)与其他脂蛋白和载脂蛋白相关性研究

目的探讨冠心病患者血浆脂蛋白(a)与HDL-C、LDL-C、载脂蛋白(apo)A-Ⅰ、apoB的相关性,评价血脂异常与冠心病的相关性。方法选择因胸痛入院的患者1011例,经冠状动脉造影确诊为冠心病患者613例作为冠心病组,非冠心病患者398例作为对照组。测定脂蛋白(a)、apoA-Ⅰ、apoB、HDL-C和LDL-C,进行相关性分析,并计算apoB/apoA-Ⅰ比值。结果冠心病组的脂蛋白(a)、LDL-C及apoB水平较对照组明显升高(P=0.000);冠心病组脂蛋白(a)水平与LDL-C、apoB呈显著正相关(r=0.135、r=0.168,P0.01),与HDL-C、apoA-Ⅰ无相关性。对照组脂蛋白(a)与LDL-C、apoB呈显著正相关(r=0.201、r=0.236,P0.01),与HDL-C、apoA-Ⅰ无相关性。apoB/apoA-Ⅰ是诊断冠心病最显著的独立危险因素(OR=31.577,95% CI:8.324～11 9.788,P=0.000),其次为脂蛋白(a)(OR=19.446,95% CI:3.831～98.716,P=0.000)。结论脂蛋白(a)与LDL-C、apoB呈正相关,提示三者均为动脉粥样硬化的危险因素;apoB/apoA-Ⅰ和脂蛋白(a)为冠心病的独立危险因素。     

Genetic and cultural inheritance of serum lipids, low and high density lipoprotein cholesterol and serum apolipoproteins A-I, A-II and B

The genetic and cultural heritability of serum cholesterol and triglyceride concentrations, as well as of the concentrations of low and high density lipoprotein cholesterol and serum apolipoproteins A-I, A-II and B, were estimated by path analysis in families selected through probands with premature myocardial infarction and in families randomly selected from the general population.

Genetic heritability was high for serum cholesterol (0.64) and low density lipoprotein cholesterol (0.67) concentrations, whereas it was lower for high density lipoprotein cholesterol level (0.42). Cultural inheritance was of less importance than genetic inheritance for all cholesterol variables. For serum triglyceride concentration genetic (0.33) and cultural (0.23) heritability was of similar significance. The results for serum apolipoproteins A-I and A-II parallelled those for HDL cholesterol. A marked intergenerational difference was found in the genetic heritability for apolipoprotein B concentration. The parental genetic heritability was 0.14, whereas the genetic heritability was 0.51 among siblings.     

High density lipoprotein (HDL) metabolism in noninsulin-dependent diabetes mellitus: measurement of HDL turnover using tritiated HDL

High density lipoprotein (HDL) kinetics were studied by injecting [3H]apoprotein A-I (apoA-I)/HDL into 12 subjects with normal glucose tolerance and 12 patients with noninsulin-dependent diabetes mellitus (NIDDM). The results indicate that the mean fractional catabolic rate (FCR) of apoA-I/HDL was significantly faster [0.63 +/- 0.07 (+/- SEM) vs. 0.39 +/- 0.02 1/day; P less than 0.001] and the apoA-I/HDL synthetic rate greater (29.4 +/- 2.9 vs. 22.9 +/- 1.3 mg/kg X day; P less than 0.02) in patients with NIDDM than in normal subjects. Furthermore, there were statistically significant inverse relationships between apoA-I/HDL FCR and plasma levels of both HDL cholesterol (r = -0.71; P less than 0.001) and apoA-I (r = -0.63; P less than 0.001). In addition, the increase in apoA-I/HDL FCR was directly related to fasting plasma glucose (r = 0.78; P less than 0.001) and insulin (r = 0.76; P less than 0.001) concentrations. These data support the view that the decrease in plasma HDL cholesterol and apoA-I levels commonly found in patients with noninsulin-dependent diabetes is due to an increase in the catabolic rate of apoA-I/HDL secondary to the defects in carbohydrate metabolism present in these patients.     

Associations among serum lipoprotein(a) levels, apolipoprotein(a) phenotypes, and myocardial infarction in patients with extremely low and high levels of serum lipoprotein(a).

A high serum lipoprotein(a) [Lp(a)] level, which is genetically determined by apolipoprotein(a) [apo(a)] size polymorphism, is an independent risk factor for coronary atherosclerosis. However, the associations among Lp(a) levels, apo(a) phenotypes, and myocardial infarction (MI) have not been studied. Patients with MI (cases, n = 101, M/F: 86/15, age: 62+/-10y) and control subjects (n = 92, M/F: 53/39, age: 58+/-14y) were classified into quintile groups (Groups I to V) according to Lp(a) levels. Apo(a) isoform phenotyping was performed by a sensitive, high-resolution technique using sodium dodecyl sulfate-agarose/gradient polyacrylamide gel electrophoresis (3-6%), which identified 26 different apo(a) phenotypes, including a null type. Groups with higher Lp(a) levels (Groups II, III, and V) had higher percentages of MI patients than that with the lowest Lp(a) levels (Group I) (54%, 56%, or 75% vs. 32%, p<0.05). Groups with different Lp(a) levels had different frequency distributions of apo(a) isoprotein phenotypes: Groups II, III, IV, and V, which had increasing Lp(a) levels, had increasingly higher percentages of smaller isoforms (A1-A4, A5-A9) and decreasingly lower percentages of large isoforms (A10-A20, A21-A25) compared to Group I. An apparent inverse relationship existed between Lp(a) and the apo(a) phenotype. Subjects with the highest Lp(a) levels (Group V) had significantly (p<0.05) higher serum levels of total cholesterol, apo B, and Lp(a). Patients with MI and the controls had different distributions of apo(a) phenotypes: i.e., more small isoforms and more large size isoforms, respectively (A1-A4/A5-A9/A10-A20/A21-A25: 35.7%/27.7%/20.8%/15.8% and 22.8%/23.9%/29.4%/23.9%, respectively). Lp(a) (parameter estimate +/- standard error: 0.70+/-0.20, Wald chi2 = 12.4, p = 0.0004), apo(a) phenotype (-0.43+/-0.15, Wald chi2 = 8.17, p = 0.004), High-density lipoprotein-cholesterol, apo A-I, and apo B were significantly associated with MI after adjusting for age, gender, and conventional risk factors, as assessed by a univariate logistic regression analysis. The association between Lp(a) and MI was independent of the apo(a) phenotype, but the association between the apo(a) phenotype and MI was not independent of Lp(a), as assessed by a multivariate logistic regression analysis. This association was not influenced by other MI- or Lp(a)-related lipid variables. These results suggest that apo(a) phenotype contributes to, but does not completely explain, the increased Lp(a) levels in MI. A stepwise logistic regression analysis with and without Lp(a) in the model identified Lp(a) and the apo(a) phenotype as significant predictors for MI, respectively.     

Higher circulating sphingosine 1-phosphate levels are associated with lower bone mineral density and higher bone resorption marker in humans

Context: Several in vivo and in vitro studies suggest that sphingosine-1-phosphate (S1P) is known to act as a coupling factor, to stimulate osteoclastogenesis, to control the migration of osteoclast precursors between the blood and bone, and to stimulate the proliferation, migration, and survival of osteoblasts. Objective: Using the determination of circulating S1P levels, we investigated which kinds of processes may be primarily affected by S1P in humans. Design and Setting: This was a cross-sectional study conducted in two clinical units in Korea. Participants: Men (n = 86), premenopausal women (n = 94), and postmenopausal women (n = 357) participated in the study. Main Outcome Measures: We measured S1P levels and their relationships with bone mineral density, biochemical bone turnover markers, and uncoupling indices. Results: S1P levels were significantly higher in the postmenopausal women than in the premenopausal women and men. High S1P concentrations were significantly associated with low bone mineral density values at some femur sites in the postmenopausal women (P = 0.015 to 0.049), at the lumbar spine in the premenopausal women (P = 0.017), and at all sites in men (P = 0.001 to 0.036) after adjustments with multiple covariates. S1P levels were positively correlated with bone resorption markers (P = 0.003 to 0.049), but not with formation markers in postmenopausal women. Higher S1P levels were associated with lower uncoupling indices (P = <0.001 to 0.048) in postmenopausal women. Conclusion: These findings suggest that S1P may primarily affect bone resorption, resulting in bone loss.     

冠脉病变与血清同型半胱氨酸及脂蛋白（a）的相关性研究

目的:观察冠心病(CHD)患者冠状动脉病变程度与血清同型半胱氨酸(Hcy)和血清脂蛋白(a)[Lp(a)]水平间的相关性。方法:选择经冠状动脉造影确诊的CHD患者108例为CHD组,其中亚组:稳定型心绞痛(SAP)37例,不稳定型心绞痛(UAP)36例,急性心肌梗死(AMI)35例,另选择82例健康体检者为健康对照组,比较两组及CHD组内各亚组血清Hcy和Lp(a)水平,分析冠状动脉病变程度与血清Hcy、Lp (a)水平的相关性。结果:与健康对照组比较,CHD组血清Hcy[(7.1±2.1)μmol/L比(15.6±5.0)μmol/L]和Lp(a)[(122.6±20.4)mg/L比(220.2±42.6)mg/L]水平均显著升高(P均=0.001);且与SAP组比较,UAP组和AMI组血清Hcy[(12.5±4.0)μmol/L比(18.1±5.9)μmol/L、(20.1±6.0)μmol/L]和Lp(a)[(150.8±30.8)mg/L比(272.8±50.3)mg/L、(280.6±52.9)mg/L]水平及Gensini评分[(15.5±8.5)分比(50.6±11.2)分、(54.3±12.8)分]均显著升高(P均=0.001);Pearson相关分析显示,CHD患者冠状动脉病变程度与血清Hcy及Lp(a)水平呈显著正相关(r=0.582、0.663,P均=0.001)。结论:血清Hcy和Lp(a)水平与CHD冠状动脉病变程度呈正相关,联合检测之有助于了解病情,并指导治疗。     

Effect of simvastatin on high density lipoprotein subfractions and apolipoproteins in Type IIa hypercholesterolemia

Summary Changes in plasma concentrations of high density lipoproteins (HDL) and triglycerides may partly explain the ability of cholesterol-lowering drugs to decrease the incidence of coronary heart disease. We measured the response of fasting plasma lipids, lipoproteins, and apolipoproteins in 46 subjects with Type IIa hypercholesterolemia treated with simvastatin for 3 months. The initial dose of simvastatin (10 mg/day) was subsequently increased up to 40 mg/day if the plasma cholesterol concentration had not fallen below 5.2 mmol/l. Plasma concentrations of HDL cholesterol and of the apolipoproteins AI and AII were increased by simvastatin. The increase in HDL cholesterol (9%) was due to increases in both subfractions (HDL₂ 17%; HDL₃ 7%), changes that would be consistent with a beneficial effect on cardiovascular risk. Simvastatin decreased plasma triglyceride concentrations by 25%. Plasma total cholesterol concentrations fell by 35% after 3 months of treatment; this fall was proportional to the initial concentration and was due almost entirely to a 45% fall in low density lipoprotein cholesterol. In contrast, plasma concentrations of lipoprotein Lp(a) were not affected by simvastatin.