Influence of cholesteryl ester transfer protein, peroxisome proliferator-activated receptor α, apolipoprotein E, and apolipoprotein A-I polymorphisms on high-density lipoprotein cholesterol, apolipoprotein A-I, lipoprotein A-I, and lipoprotein A-I:A-II concentrations: the Prospective Epidemiological Study of Myocardial Infarction study

The plasma level of high-density lipoprotein cholesterol (HDL-C) is known to be inversely associated with cardiovascular risk. However, besides lifestyle, gene polymorphism may influence the HDL-C concentration. The aim of this study was to investigate the possibility of interactions between CETP, PPARA, APOE, and APOAI polymorphisms and HDL-C, apolipoprotein (apo) A-I, lipoprotein (Lp) A-I, and Lp A-I:A-II in a sample selected from the Prospective Epidemiological Study of Myocardial Infarction (PRIME) study population who remained free of cardiovascular events over 5 years of follow-up. Healthy individuals (857) were randomly selected for genotyping the PRIME study subjects. The population was selected so as to provide 25% of subjects in the lowest tertile of HDL-C (≤28 mg/dL) in the whole PRIME study sample, 25% of subjects in the highest tertile of HDL-C (≥73 mg/dL), and 50% of subjects in the medium tertile of HDL-C (28-73 mg/dL). Genotyping was performed by using a polymerase chain reaction system with predeveloped TaqMan allelic discrimination assay. The CETP A373P rare allele c was less frequent in the group of subjects with high HDL-C, apo A-I, Lp A-I, and Lp A-I:A-II concentrations. Apolipoprotein A-I and Lp A-I were also found to be higher in the presence of the ?2 allele coding for APOE. The effect of the CETP A373P rare allele c on HDL-C was independent of all tested parameters except triglycerides. The respective effect of these polymorphisms and triglycerides on cardiovascular risk should be evaluated prospectively.     

Serum high density lipoprotein cholesterol, apolipoprotein A-I, A-II and B levels in Singapore ethnic groups

The mortality rate from CAD in Indians is more than 3 times that in the Chinese and Malays in the population of Singapore. The serum total, HDL cholesterol and apolipoprotein levels (Apo A-I, Apo A-II and Apo B) were studied in a group of 344 healthy male adults from the 3 ethnic groups. Indians had a significantly lower level of HDL-cholesterol (38.4 +/- 9.8 mg/dl) than the Chinese (42.7 +/- 8.9 mg/dl) (P less than 0.005). The Apo A-I levels were higher in the Chinese (115.1 +/- 14.8 mg/dl) than in the Indians (108.6 +/- 28.8 mg/dl), but the difference was not statistically significant. The Chinese also had higher levels of Apo A-II (48.1 +/- 7.2 mg/dl) compared to those in the Indians (38.6 +/- 6.4 mg/dl) and Malays (38.0 +/- 4.9 mg/dl) (P less than 0.001). The ratio of Apo A-I/Apo B level was also higher in the Chinese (1.28) than in the Indians and Malays (1.09). Higher levels of Apo B and lower levels of HDL-cholesterol, Apo A-I and Apo A-II in Indians may partly explain the higher incidence of CAD in Indians.     

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.     

Association of the apolipoprotein B/apolipoprotein A-I ratio and low-density lipoprotein cholesterol with insulin resistance in a Chinese population with abdominal obesity

The aim of this study is to assess the relationships among the apolipoprotein B/apolipoprotein A-I ratio (apoB/apoA-I ratio), low-density lipoprotein cholesterol (LDL-C) and insulin resistance (IR) in a Chinese population with abdominal obesity. This is a population-based, cross-sectional study of 3,945 men and 2,141 women with abdominal obesity. Individuals were referred to a primary health service and recruited for analysis. IR was measured using a homeostasis model assessment of insulin resistance (HOMA2-IR) with a HOMA2 calculator. Metabolic syndrome (MetS) was diagnosed using International Diabetes Federation (IDF) criteria. Comparing the apoB/apoA-I ratio and lipid indices using the HOMA2-IR showed that the ratio, LDL-C, total cholesterol level (TC) and triglyceride level (TG) were higher; and the high-density lipoprotein cholesterol level (HDL-C) was lower in the fourth than in the first quartile in both sexes (p????0.001). After adjustment for age, HOMA2-IR was positively correlated with the apoB/apoA-I ratio, LDL-C, TC and TG; and negatively correlated with HDL-C in men (all p?<?0.0001). HOMA2-IR was also positively correlated with the apoB/apoA-I ratio, LDL-C, TC and TG; and negatively correlated with HDL-C in women (all p?<?0.01). After adjustment for age and LDL-C, HOMA2-IR was found to be correlated with the apoB/apoA-I ratio in both men and women (r?=?0.066 and 0.116, p?<?0.0001). After adjustment for age and the apoB/apoA-I ratio, HOMA2-IR was correlated with LDL-C in men and women (r?=?0.063 and 0.044, p?<?0.0001 and p?=?0.0431, respectively). Gender, age, LDL-C, BMI, HOMA2-IR and apoB/apoA-I were the covariates independently associated with presence of the MetS (Odds ratio, OR: 2.183, 1.034, 1.013, 1.157, 1.726 and 1.570, respectively; all p?<?0.05). In conclusion, the study showed that the apoB/apoA-I ratio and LDL-C were positively correlated with IR. Excluding reciprocal interactions, the apoB/apoA-I ratio and LDL-C were still significantly correlated with IR, but the apoB/apoA-I ratio showed a greater correlation with IR than LDL-C in women with abdominal obesity, compared with men with abdominal obesity. Both LDL-C and apoB/apoA-I were independent risk factors of MetS, and the apoB/apoA-I ratio was stronger in this regard than LDL-C for this obese population.     

Hyperhomocysteinemia decreases circulating high-density lipoprotein by inhibiting apolipoprotein A-I Protein synthesis and enhancing HDL cholesterol clearance

We previously reported that hyperhomocysteinemia (HHcy), an independent risk factor of coronary artery disease (CAD), is associated with increased atherosclerosis and decreased plasma high-density lipoprotein cholesterol (HDL-C) in cystathionine beta-synthase-/apolipoprotein E-deficient (CBS(-/-)/apoE(-/-)) mice. We observed that plasma homocysteine (Hcy) concentrations are negatively correlated with HDL-C and apolipoprotein A1 (apoA-I) in patients with CAD. We found the loss of large HDL particles, increased HDL-free cholesterol, and decreased HDL protein in CBS(-/-)/apoE(-/-) mice, and attenuated cholesterol efflux from cholesterol-loaded macrophages to plasma in CBS(-/-)/apoE(-/-) mice. ApoA-I protein was reduced in the plasma and liver, but hepatic apoA-I mRNA was unchanged in CBS(-/-)/apoE(-/-) mice. Moreover, Hcy (0.5 to 2 mmol/L) reduced the levels of apoA-I protein but not mRNA and inhibited apoA-1 protein synthesis in mouse primary hepatocytes. Further, plasma lecithin:cholesterol acyltransferase (LCAT) substrate reactivity was decreased, LCAT specific activity increased, and plasma LCAT protein levels unchanged in apoE(-/-)/CBS(-/-) mice. Finally, the clearance of plasma HDL cholesteryl ester, but not HDL protein, was faster in CBS(-/-)/apoE(-/-) mice, correlated with increased scavenger receptor B1, and unchanged ATP-binding cassette transporter A1 protein expression in the liver. These findings indicate that HHcy inhibits reverse cholesterol transport by reducing circulating HDL via inhibiting apoA-I protein synthesis and enhancing HDL-C clearance.     

Effect of alcohol intake and exercise on plasma high-density lipoprotein cholesterol subfractions and apolipoprotein A-I in women

Abstinence from alcohol consumption for 3 weeks was followed by 3 weeks of wine intake in 18 inactive and 18 physically active premenopausal women (runners). The runners weighed less and had higher plasma high-density lipoprotein (HDL) cholesterol and lower low-density lipoprotein cholesterol levels than the inactive women. There were no differences between groups in plasma total cholesterol, triglyceride and apolipoprotein A-I concentrations. Runners had higher plasma HDL2 cholesterol concentrations than inactive women (34 +/- 17 vs 19 +/- 12 mg/dl), but HDL3 cholesterol concentration did not differ between the groups (41 +/- 10 vs 39 +/- 9 mg/dl). Addition of 35 g/day of ethanol for 3 weeks did not result in a significant change in either group for any of the variables measured. The amount of exercise appears to be a more important determinant of plasma lipoproteins and apolipoprotein A-I than alcohol intake in premenopausal women.     

Association of serum apolipoprotein A-I (but not high-density lipoprotein cholesterol) with healed myocardial infarction in men independent of serum insulin and C-peptide

Low serum levels of high-density lipoprotein (HDL) cholesterol or apolipoprotein A-I and high serum levels of insulin increase the risk of coronary heart disease (CHD) and can indicate insulin resistance. We tested the strength, independence, and interactions of associations between HDL cholesterol (or apolipoprotein A-I), insulin (or C-peptide), glucose, and CHD in 95 male nondiabetic patients with CHD who were <60 years old, in 92 probands from the PROCAM study, and in 61 non-cardiologic patients; all subjects were matched by age, body mass index, and smoking habits. Systemic hypertension (odds radio [OR] 2.8, 95% confidence intervals [CI] 1.6 to 4.8), high serum levels of glucose (OR 2.3, 95% CI 1.6 to 4.8), insulin (OR 2.1, 95% CI 1.3 to 3.6), and C-peptide (OR 4.1, 95% CI 2.2 to 7.5) as well as low serum levels of HDL cholesterol (OR 2.0, 95% CI 1.1 to 3.5) or apolipoprotein A-I (OR 3.9, 95% CI 2.1 to 7.1) had significant associations with CHD. At multivariate analysis, systolic blood pressure, glucose, apolipoprotein A-I, and C-peptide, but not HDL cholesterol and insulin, had consistent independent associations with CHD. Thus, the combined measurement of apolipoprotein A-I and C-peptide may improve the identification of nondiabetic patients at increased risk for CHD.     

Differential effects of simvastatin and atorvastatin on high-density lipoprotein cholesterol and apolipoprotein A-I are consistent across hypercholesterolemic patient subgroups

BACKGROUND: In addition to lowering plasma levels of low-density lipoprotein cholesterol (LDL-C), statins also raise high-density lipoprotein cholesterol (HDL-C). HYPOTHESIS: Recent studies have shown that treatment with simvastatin results in larger increases in HDL-C than those seen with atorvastatin. The results of three clinical studies are analyzed, comparing the effects of simvastatin and atorvastatin on HDL-C and apolipoprotein A-I (apo A-I) in the total cohort and in several subgroups of hypercholesterolemic patients. The three studies were all multicenter, randomized clinical trials that included simvastatin (20-80 mg) and atorvastatin (10-80 mg) treatment arms. The subgroup analyses performed were gender; age (< 65 and > or = 65 years); baseline HDL-C (male: < 40 or > or = 40 mg/dl; female: < 45 or > or = 45 mg/dl), baseline LDL-C (< 160 or > or = 160 mg/dl), and baseline triglycerides (< 200 or > or = 200 mg/dl). RESULTS: Both drugs produced similar increases in HDL-C levels at low doses; however, at higher drug doses (40 and 80 mg), HDL-C showed a significantly greater increase with simvastatin than with atorvastatin (p < 0.05 to < 0.001). Therefore, while HDL-C remained consistently elevated across all doses of simvastatin, there appeared to be a pattern of decreasing HDL-C with an increasing dose of atorvastatin. A similar negative dose response pattern was also observed with apo A-I in atorvastatin-treated patients, suggesting a reduction in the number of circulating HDL particles at higher doses. Both drugs reduced LDL-C and triglycerides in a dose-dependent fashion, with atorvastatin showing slightly greater effects. The differential effects of atorvastatin and simvastatin on HDL-C and apo A-I were observed for both the whole study cohorts and all subgroups examined; thus, no consistent treatment-by-subgroup interactions were observed. CONCLUSION: The data presented show that, across different hypercholesterolemic patient subgroups, simvastatin increases HDL-C and apo A-I more than atorvastatin at higher doses, with evidence of a negative dose response effect on HDL-C and apo A-I with atorvastatin, but not simvastatin.     

Plasma apolipoprotein C-III transport in centrally obese men: associations with very low-density lipoprotein apolipoprotein B and high-density lipoprotein apolipoprotein A-I metabolism

CONTEXT: Apolipoprotein (apo) C-III is associated with hypertriglyceridemia and progression of cardiovascular disease. Plasma apoC-III is elevated in centrally obese men, and we hypothesized that the kinetics of apoC-III are disturbed in these subjects. OBJECTIVE: We developed a compartmental model to determine very low-density lipoprotein (VLDL) and high-density lipoprotein (HDL) apoC-III metabolic parameters in centrally obese men and investigated the associations with VLDL-apoB and HDL-apoA-I kinetics. STUDY DESIGN: Apolipoprotein kinetics was determined using stable isotope techniques and compartmental modelling in 39 centrally obese and 12 nonobese men. RESULTS: Compared with nonobese subjects, centrally obese subjects had increased plasma apoC-III concentration (160 +/- 5 mg/liter vs. 103 +/- 9 mg/liter, P < 0.001), reflecting increased concentrations of both VLDL-apoC-III and HDL-apoC-III. These related to increased production rate (PR) of VLDL-apoC-III (2.12 +/- 0.14 vs. 1.56 +/- 0.29 mg/kg x d, P < 0.05) and reduced fractional catabolic rate (FCR) of both VLDL- and HDL-apoC-III (0.70 +/- 0.02 pools/d vs. 0.82 +/- 0.05 pools/d, P < 0.05). In centrally obese men, VLDL-apoC-III concentration was significantly (P < 0.05) associated with VLDL-apoB concentration and PR as well as HDL-apoA-I FCR and PR and inversely with VLDL-apoB FCR. HDL-apoC-III concentration was significantly (P < 0.05) associated with the concentrations of both VLDL-apoB and HDL-apoA-I, the FCR, and the PR of HDL-apoA-I and inversely with the VLDL-apoB FCR. In multiple regression analysis, both VLDL-apoC-III and HDL-apoC-III concentrations were significantly associated with HDL-apoA-I FCR. CONCLUSIONS: In centrally obese men, elevated VLDL-apoC-III and HDL-apoC-III concentrations are a consequence of elevated production and decreased catabolism of VLDL-apoC-III and reduced catabolism of HDL-apoC-III, respectively. These defects are associated with disturbances in VLDL-apoB and HDL-apoA-I metabolism.     

High-density apolipoprotein A-I and A-II kinetics in relation to regional adiposity

High-density lipoprotein (HDL) cholesterol and apolipoprotein (apo) A-I concentrations decrease with increasing central adiposity. The present study investigated possible mechanisms for these effects by examining the relationship between body mass index, regional adiposity, and HDL apo A-I and A-II metabolism. Fifteen sedentary men and 10 male endurance athletes aged 22 to 44 served as subjects. HDL apo A-I and A-II metabolism was examined using 125I-labeled autologous HDL. Chest and thigh skinfold thickness and the ratio of chest to thigh skinfold thickness were used as indices of regional adiposity. The relationship of adiposity to HDL metabolism was examined using correlational and multiple regression analysis. In both subject groups, the fractional catabolic rate of apo A-I and A-II increased with increasing chest skinfold thickness and chest to thigh skinfold ratio (.43 < r2 < .66). This effect was partially independent of triglyceride or HDL cholesterol concentrations. Apo A-I and A-II fractional catabolic rates increased with increasing body mass index only in the sedentary men. Concentrations and synthetic rates (mg.d-1.kg-1) of apo A-I and A-II were not consistently related to body mass index or regional adiposity. Peripheral adiposity assessed by thigh skinfold thickness was not correlated with any parameter of apo metabolism. We conclude that HDL apo A-I and A-II catabolism increases with increasing central adiposity.     

High apolipoprotein B with low high-density lipoprotein cholesterol and normal plasma triglycerides and cholesterol

Increased numbers of small, dense low-density lipoprotein particles may be present in patients with low high-density lipoprotein cholesterol and normal plasma triglycerides and cholesterol. Measurment of apolipoprotein B is the key to diagnosis and such patients should be considered for statin therapy.     

Effect of 17 alpha-ethinylestradiol on the catabolism of high-density lipoprotein apolipoprotein A-I in the rat

The in vivo metabolism and tissue sites of catabolism of high-density lipoproteins (HDL), labelled specifically in the apolipoprotein (apo) A-I moiety, were studied in rats treated with 17 alpha-ethinylestradiol (EE) for 5 days. Apo A-I was labelled either with O-(4-diazo-3-[125I]iodobenzoyl)sucrose, a non-degradable labelling compound, or with 131ICl. It was found that EE treatment decreases the serum cholesterol concentration to 10 mg/dl and stimulates the serum decay of apo A-I labelled HDL. The latter effect could be attributed to an increased catabolism of apo A-I labelled HDL in the liver. The increased rates of the serum decay and tissue uptake of apo A-I labelled HDL in EE-treated rats were not affected by a bolus injection of unlabelled human low-density lipoprotein (LDL), administered at the time of the injection of the labelled HDL. When the serum cholesterol concentration was raised to physiological levels by a bolus injection of unlabelled rat HDL, both the serum decay and the tissue uptake of apo A-I labelled HDL were almost completely restored to conditions encountered in control animals. In vitro binding experiments showed that liver membranes obtained from EE-treated rats demonstrated a 6-fold increased specific binding of human 125I-LDL, but virtually unchanged specific binding of rat 125I-HDL, as compared with liver membranes obtained from control rats. It is concluded that rat HDL apo A-I catabolism is hardly mediated by the apo B/E receptor induced by EE treatment.     

Should triglycerides and the triglycerides to high-density lipoprotein cholesterol ratio be used as surrogates for insulin resistance?

The aims of the present study were to examine whether triglycerides (TG) and the triglyceride to high-density lipoprotein cholesterol ratio (TG/HDL-C) could predict insulin resistance in healthy African Americans and whites. This cross-sectional study included 99 African American and 50 white men and women between 18 and 45 years of age with body mass indexes between 18.5 and 38.0 kg/m². Anthropometric measures were obtained; and overnight fasting blood was collected for TG, HDL-C, glucose, and insulin. Insulin resistance was defined by fasting insulin concentration of at least 13.13 μU/mL and homeostasis model assessment of insulin resistance (HOMA-IR) of at least 2.5. Receiver operating characteristic curves were used to analyze the data. African Americans and whites had comparable demographic and anthropometric measures. Fasting insulin was higher in African Americans (12.4 ± 7.8 μU/mL) than whites (10.2 ± 7.5 μU/mL), but HOMA-IR did not differ significantly (African Americans, 2.9 ± 2.0; whites, 2.4 ± 1.9). Triglycerides and TG/HDL-C were significantly lower in African Americans (TG, 68.2 ± 43.3 mg/dL; TG/HDL-C, 1.8 ± 2.1) compared with whites (TG, 105.4 ± 55.2 mg/dL; TG/HDL-C, 2.8 ± 1.8). Area under the receiver operating characteristic curves revealed that both TG and TG/HDL-C were acceptable markers of insulin resistance, as defined by fasting insulin concentration, in whites, 0.770 and 0.765, respectively, but poor predictors in African Americans, 0.633 and 0.651, respectively. Similarly, TG and TG/HDL-C were acceptable in predicting insulin resistance, as measured by HOMA-IR, in whites, 0.763 and 0.770, respectively, but poor in predicting HOMA-IR in African Americans, with areas of 0.625 and 0.639, respectively. In conclusion, the relationship between TG and TG/HDL-C with insulin resistance differs by ethnicity; and using TG and TG/HDL-C to predict insulin resistance in African Americans would not be appropriate.     

Comparison of low-density lipoprotein cholesterol/high-density lipoprotein cholesterol and total cholesterol/high-density lipoprotein cholesterol for the prediction of thin-cap fibroatheroma determined by intravascular optical coherence tomography

BackgroundThe correlation among the ratios of low-density lipoprotein cholesterol/high-density lipoprotein cholesterol (LDL-C/ HDL-C), total cholesterol/high-density lipoprotein cholesterol (TC/HDL-C) and thin-cap fibroatheroma has not yet been established.MethodsIt was a single center, retrospective observational study. In total, we recruited 421 patients (82.4% men; mean age 65.73 ± 10.44 years) with one culprit vessel which determined by intravascular optical coherence tomography (OCT). The thinnest-capped fibroatheroma (TCFA) group was defined as lipid contents in > 2 quadrants, with the thinnest fibrous cap measuring less than 65 μm. Univariate and multivariate logistic regression were carried out to explore the relationship between lipoprotein ratios, TCFA and other characteristics of plaque. To compare different ratios, the area under curve (AUC) of receiver-operating characteristic (ROC) curve was assessed.ResultsOCT was performed in 421 patients (TCFA group (n = 109), non-TCFA group (n = 312)). LDL-C/HDL-C in the TCFA group was significantly higher than in the non-TCFA group (2.95 ± 1.20 vs. 2.43 ± 0.92, P < 0.05), as was TC/LDL in TCFA and non-TCFA group (4.57 ± 1.58 vs. 4.04 ± 1.13, P < 0.05). Both LDL-C/HDL-C (OR: 1.002 (1.002-1.003), P < 0.05) and TC/HDL-C (OR: 1.001 (1.001-1.004), P < 0.05) were considered independent factors for the prediction of TCFA according to the logistic regression. Based on the AUC comparison, LDL-C/ HDL-C and TC/HDL-C had no significant difference statistically (LDL-C/HDL-C AUC: 0.63; TC/HDL-C AUC: 0.61; P = 0.10) for the prediction of TCFA.ConclusionsLDL-C/HDL-C and TC/HDL-C could be the independent factors for predicting the presence of TCFA, indicating coronary plaque vulnerability in CAD patients. Moreover, TC/HDL-C also showed a comparative performance for the prediction of TCFA as LDL-C/HDL-C.     

Effect of low-dose niacin on high-density lipoprotein cholesterol and total cholesterol/high-density lipoprotein cholesterol ratio

Niacin significantly alters blood lipid concentrations but its use has been limited because of clinically disturbing side effects. In an attempt to circumvent these drawbacks, 55 patients with cardiovascular disease were given low-dose long-acting niacin, 1 g/d. Treatment was continued for a mean of 6.7 months and lipid values were compared with a non-treated group of 17 patients followed for a mean of 6.3 months. Lipid values did not change in the nontreated group. In the niacin-treated group total cholesterol and triglyceride levels also did not significantly change. High-density lipoprotein (HDL) cholesterol level rose 31% from 1.01 +/- 0.31 mmol/L to 1.32 +/- 0.31 mmol/L and total cholesterol/HDL cholesterol ratio was reduced 27% from 6.4 +/- 1.9 to 4.7 +/- 1.3. Despite these results, 40% of the patients left the study mainly because of side effects. Apart from one patient who developed overt diabetes, of questionable relationship to niacin, no patient developed serious side effects such as jaundice or peptic ulcer as seen with much higher doses of the drug. Although often difficult to administer to patients, niacin, particularly in low dose, deserves consideration as an inexpensive agent especially useful for elevating HDL cholesterol level and altering the total cholesterol/HDL cholesterol ratio.