Increased plasma and renal clearance of an exchangeable pool of apolipoprotein A-I in subjects with low levels of high density lipoprotein cholesterol.

Plasma levels of HDL apo A-I are reduced in individuals with low HDL cholesterol (HDL-C) concentrations as a result of increased fractional catabolic rates (FCRs). To determine the basis for the high apo A-I FCRs, seven subjects with low HDL-C levels (31.0 +/- 4.3 mg/dl) were compared with three subjects with high HDL-C levels (72.0 +/- 4.5 mg/dl). Each subject received autologous HDL that was labeled directly by the iodine-monochloride method (whole-labeled) and autologous HDL that was labeled by exchange with homologous radiolabeled apo A-I (exchange-labeled). Blood was obtained for 2 wk, specific activities determined, and FCRs (d-1 +/- SD) estimated. In every subject, whether in the low or high HDL-C group, the exchange-labeled FCR was greater than the whole-labeled FCR. The exchange-labeled FCR was higher in the low HDL-C group (0.339 +/- 0.043) versus the high HDL-C group (0.234 +/- 0.047; P < 0.009). The whole-labeled FCR was also greater in the low HDL-C group (0.239 +/- 0.023) versus the high HDL-C group (0.161 +/- 0.064; P < 0.02). In addition, in both low and high HDL groups ultracentrifugation resulted in more radioactivity in d > 1.210 (as percentage of total plasma counts per minute) with the exchange-labeled tracer than with the whole-labeled tracer (12.55 +/- 4.95% vs. 1.02 +/- 0.38%; P < 0.003). With both HDL tracers, more radioactivity was found in d > 1.210 in the low versus the high HDL-C groups. When apo A-I catabolism was studied by perfusing isolated rabbit kidneys with whole-labeled HDL, there was twice as much accumulation (cpm/g cortex) of HDL apo A-I isolated from subjects with low HDL-C than from subjects with high HDL-C (P < 0.0025). Finally, HDL that had been isolated from subjects with high levels of HDL-C was triglyceride enriched and exposed to partially purified lipases before perfusion through kidneys. Threefold more apo A-I from modified HDL accumulated in the cortex compared with the unmodified preparation (P < 0.007). The results of these in vivo and ex vivo studies indicate that individuals with low HDL-C levels have more loosely bound, easily exchanged apo A-I and that this exchangeable apo A-I is more readily cleared by the kidney.     

Lipoproteins and apolipoproteins in young nonobese Arab women with NIDDM treated with insulin

The effects of insulin on the lipid values of nonobese non-insulin-dependent diabetic (NIDDM) Arab women requiring insulin was investigated to find whether these patients have the same coronary artery risk factor related to lipid levels. In this study, 55 NIDDM women on insulin therapy (mean age 28 +/- 8.1 yr and duration of disease 5 +/- 1.2 yr) and 70 control subjects (matched for sex, age, and body mass index) were studied for their plasma levels of lipids, lipoproteins, and apolipoproteins. Concentrations of total cholesterol, very-low-density lipoprotein cholesterol, low-density lipoprotein (LDL) cholesterol, triglyceride (TG), LDL TG, high-density lipoprotein triglyceride (HDL TG), phospholipid, glucose, glycosylated hemoglobin (HbAtc), apolipoprotein B (apoB), LDL-apoB, and apoB/apoAl were significantly elevated in diabetic women compared with control subjects. There was no significant change in the levels of apoAll in plasma and lipoprotein fractions. Concentrations of HDL cholesterol (chol), HDL2-chol, HDL3-chol, plasma apoAl, HDL2-apoAl, HDL3-apoAl, and HDL-apoAl were significantly lower in diabetic women than in control subjects. There was no significant correlation between glucose or HbAtc and most of the lipids, lipoprotein lipids, and apolipoproteins measured. Despite normal body weight and insulin therapy, abnormalities in lipids, lipoprotein lipids, and apoB persisted in NIDDM patients compared with control subjects. Our data may favor an enhanced affinity toward atherosclerosis in these patients.     

Abnormal capacity to induce cholesterol efflux and a new LpA-I pre-beta particle in type 2 diabetic patients

In this study, we first characterized the lipoprotein components of serum samples obtained from a group of well-controlled diabetic patients and from healthy subjects in fasting and postprandial states. We then explored some aspects of reverse cholesterol transport in the same population. Patients showed high levels of fasting triglycerides, postprandial triglyceride responses and LpC-III levels (3.18+/-0.86 vs 2.17+/-0.54 mg/dl, P < 0.001). There were also positive correlations between LpC-III and fasting triglycerides (r = 0.82, P < 0.001), total triglyceride area (r = 0.75, P < 0.001) and incremental triglyceride area (r = 0.54, P < 0.001). HDL-C and apo A-I were significantly decreased in diabetic patients due to a selective reduction in LpA-I subfraction, whose antiatherogenic role is generally accepted (37.4+/-8.0 vs 49.2+/-12.5 mg/dl, P < 0.001). In addition, HDL from patients proved to be triglyceride enriched and cholesteryl ester depleted, alterations which were further amplified in the postprandial state. The molar ratio HDL-C/apo A-I + apo A-II, already defined as a predictor of apo A-I fractional catabolic rate, was significantly diminished in the patient group (15.1+/-2.2 vs 20.8+/-3.3, P < 0.001), thus suggesting an accelerated catabolism of apo A-I. For the first time, we describe here the presence of a small apo A-I-containing particle, isolated by two-dimensional electrophoresis and characterized by immunoblotting, only in samples from diabetic patients. This particle that we named pre-beta0, has an apparent molecular weight of 40 kDa. As regards the capacity of serum samples to promote cholesterol efflux from [3H]cholesterol-labeled Fu5AH rat hepatoma cells, patient samples were found to induce significantly lower cholesterol efflux than controls only in the postprandial state (21.2+/-3.3 vs 23.8+/-1.8%, P = 0.012). The presence of pre-beta0 in samples from diabetic patients might therefore be associated to an altered capacity of these serum samples to promote cellular cholesterol efflux. Overall, these abnormalities may contribute to a delay in the reverse cholesterol transport pathway in type 2 diabetic patients.     

A low-fat diet decreases high density lipoprotein (HDL) cholesterol levels by decreasing HDL apolipoprotein transport rates.

Diets that reduce atherosclerosis risk lower levels of HDL cholesterol (HDL-C), but the significance of this is unclear. To better understand the mechanism of this phenomenon we studied the turnover of HDL apolipoproteins A-I and A-II in 13 subjects on two contrasting metabolic diets. Upon changing from high to low intake of saturated fat and cholesterol the mean HDL-C decreased 29% from 56 +/- 13 (SD) to 40 +/- 10 mg/dl, while apo A-I levels fell 23% from 139 +/- 22 to 107 +/- 22 mg/dl (both P less than 0.001). Mean apo A-II levels did not change. The fractional catabolic rate (FCR) of apo A-I increased 11% from 0.228 +/- 0.048 to 0.254 +/- 0.063 pools/d, while its absolute transport rate (TR) decreased 14% from 12.0 +/- 2.7 to 10.3 +/- 3.4 mg/kg per d (both P = 0.005). The decrease in HDL-C and apo A-I levels correlated with the decrease in apo A-I TR (r = 0.79 and 0.83, respectively; P less than 0.001), but not with the increase in apo A-I FCR (r = -0.04 and -0.02, respectively). In contrast, within each diet the HDL-C and apo A-I levels were inversely correlated with apo A-I FCR both on the high-fat (r = -0.85 and -0.77, P less than 0.001 and = 0.002, respectively) and low-fat diets (r = -0.67 and -0.48, P = 0.012 and 0.098, respectively) but not with apo A-I TR. In summary, diet-induced changes in HDL-C levels correlate with and may result from changes in apo A-I TR. In contrast, differences in HDL-C levels between people on a given diet correlate with and may result from differences in apo A-I FCR. Therefore, the mechanism of dietary effects on HDL levels differs substantially from the mechanism explaining the differences in levels between individuals on a fixed diet. In assessing coronary heart disease risk, it may be inappropriate to conclude that diet-induced decreases in HDL are equivalent to low HDL within a given diet.     

Low-dose effect of simvastatin (MK-733) on serum lipids, lipoproteins, and apolipoproteins in patients with hypercholesterolemia

The effects of simvastatin (MK-733), a competitive inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase, on serum lipids, lipoproteins, and apolipoproteins were investigated in 29 patients (12 men, 17 women, aged 37 to 73) with moderate to severe hypercholesterolemia. It was given in doses of 2.5 mg/day for four months and 5 mg/day for the succeeding four months. Total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and apolipoprotein (apo) B decreased by 18% (263 +/- 7 mg/dl to 216 +/- 7 mg/dl, P less than 0.01), 24% (180 +/- 7 mg/dl to 136 +/- 7 mg/dl, P less than 0.01), and 21% (133 +/- 4 mg/dl to 104 +/- 3 mg/dl, P less than 0.01), respectively, four months after treatment. Similar reductions (17%, 24%, and 23%, respectively, P less than 0.01) were observed at eight months. A significant reduction in triglyceride (TG) was observed (173 +/- 15 mg/dl to 136 +/- 11 mg/dl at eight months, P less than 0.01), as was a significant increase in serum high-density lipoprotein cholesterol (HDL-C) (48 +/- 2 mg/dl to 52 +/- 2 mg/dl at eight months, P less than 0.01). However, apo AI and apo AII remained unchanged. Atherogenic indices of (TC--HDL-C)/ HDL-C, LDL-C/HDL-C, and apo B/Apo AI ratios were significantly (P less than 0.01) reduced after treatment. No significant changes were observed in lipoprotein lipase, hepatic TG lipase, and lecithin: cholesterol acyltransferase (LCAT) activities. Simvastatin was well tolerated and no critical side effects were noted in the eight-month study period. These data indicate that simvastatin, even at a low dose of 2.5 to 5 mg daily, causes consistent reductions in serum TC, LDL-C, apo B, and TG, and a rise in HDL-C and antiatherogenic lipoproteins.     

An interaction between the human cholesteryl ester transfer protein (CETP) and apolipoprotein A-I genes in transgenic mice results in a profound CETP-mediated depression of high density lipoprotein cholesterol levels.

We have previously described two transgenic mouse lines, one heterozygous for the human apo A-I gene and the other heterozygous for a human cholesteryl ester transfer protein (CETP) minigene driven by the mouse metallothionein-I gene promoter. In the current study, these two lines were crossed producing control, HuCETPTg, HuAITg, and HuAICETPTg mice to study the influence of CETP on HDL cholesterol levels, particle size distribution, and metabolism in animals with mouse and human-like HDL. In the HuCETPTg and HuAICETPTg animals, zinc induction approximately doubled plasma CETP activity, with no activity in plasma from the control and HuAITg animals. The only significant effect of CETP on lipoprotein subfraction cholesterol concentrations was for HDL-C. Compared to control animals, HuCETPTg animals had lower HDL-C, 20% before and 35% after Zn induction, and compared to HuAITg animals, HuAICETPTg animals had lower HDL-C, 35% before and 66% after Zn induction. Control and HuCETPTg HDL consist primarily of a single size population with a mean diameter of 10.00 +/- 0.10 nm and 9.71 +/- 0.05 nm, respectively. HuAITg HDL consists primarily of three distinct HDL size subpopulations with peak diameters of 10.35 +/- 0.08 nm, 8.80 +/- 0.06 nm, 7.40 +/- 0.10 nm, and HuAICETPTg HDL also consists primarily of three distinct HDL size subpopulations with peak diameters of 9.87 +/- 0.05 nm, 8.60 +/- 0.10 nm, 7.30 +/- 0.15 nm before, and 9.71 +/- 0.08 nm, 8.50 +/- 0.11 nm, 7.27 +/- 0.15 nm after zinc induction, respectively. Western blotting analysis of nondenaturing gradient gels of plasma with a monoclonal antibody to CETP indicated that in HuCETPTg and HuAICETPTg mice, 22 and 100%, respectively, of the CETP was HDL associated. Turnover studies with HDL doubly labeled with 125I apo A-I and 3H cholesteryl linoleate indicated that the CETP-induced fall in HDL-C was associated with increased HDL-cholesterol ester fractional catabolic rate in both the absence and presence of human apo A-I, suggesting CETP-mediated transfer of HDL-cholesterol ester to apo B-containing lipoproteins. In summary, these studies suggest that CETP has a much more profound effect on HDL cholesterol levels in transgenic animals expressing human apo A-I. This may be due to an enhanced interaction of CETP with human compared to mouse apo A-I or to the HDL particles they produce.     

The Measurement of Apolipoprotein A-I and A-II Levels in Men and Women by Immunoassay

To study apolipoprotein A-II, a simple, precise, and accurate immunodiffusion assay was developed and applied in a population sample of industrial employees. Apolipoprotein A-II (A-II) did not increase with age in men (r = -0.20, n = 172), but showed a slight increase with age in women (0.1 mg/dl per yr, r = 0.20, n = 188). A-II correlated significantly with apolipoprotein A-I (A-I) (r = 0.71) and high density lipoprotein (HDL) cholesterol (men, r = 0.64; women, r = 0.49). The A-I/A-II ratio was significantly related to HDL cholesterol (men, r = 0.29; women, r = 0.44). Women on no medication (n = 92) had A-II levels similar to men (34+/-5 and 33+/-5 mg/dl, mean+/-SD, respectively), whereas women on oral contraceptives or estrogens had significantly higher levels (39+/-6 mg/dl, n = 75, P < 0.01). The plasma A-I/A-II weight ratio was 3.6+/-0.4 for men and 3.8+/-0.5 for women. In the d = 1.10-1.21 subfraction, both males and females had similar A-I, A-II, and HDL cholesterol levels (men: mean, 97, 27, and 32 mg/dl, respectively; women: mean, 104, 28, and 36 mg/dl, respectively). Women had approximately twice the amount of A-I, A-II, and HDL cholesterol than men in the d = 1.063-1.10 fraction (men: mean, 10, 2, and 10 mg/dl, respectively; women: mean, 24, 4, and 19 mg/dl, respectively). The A-I/A-II weight ratio in the d = 1.063-1.10 fraction (men, 5.1+/-0.7; women, 6.1+/-1.3) was significantly greater (P < 0.01) than that in the d = 1.10-1.21 fraction (men, 3.7+/-0.2; women, 3.8+/-0.2). Furthermore, the weight ratio of cholesterol to total apoprotein A in the d = 1.063-1.10 fraction (men, 0.75+/-0.09; women, 0.67+/-0.05) was significantly higher (P < 0.01) than that found in the d = 1.10-1.21 fraction (men, 0.26+/-0.04, women, 0.28+/-0.05). Thus, the compositions of HDL hydrated density subclasses are significantly different from each other. These results suggest that the differences in HDL between men and women are due primarily to differences in the relative proportions of HDL subclasses rather than to the intrinsic differences in HDL structure.     

Effect of captopril on high-density lipoprotein subfractions in patients with mild to moderate essential hypertension

Changes in serum lipids, apolipoproteins, and lipoproteins including high-density lipoprotein (HDL) subfractions following administration of captopril in patients with hypertension were studied. Captopril (25 mg twice daily) was administered over a 12-week period to 17 patients with mild to moderate essential hypertension. Captopril was observed to significantly reduce both systolic and diastolic blood pressure, as well as to increase HDL2- cholesterol (HDL2-C) and to decrease HDL3-cholesterol (HDL3-C); however, no significant changes in total HDL-C were recognized. Total cholesterol, low-density lipoprotein cholesterol, triglyceride, apolipoprotein (apo) A-I, apo A-II, apo B, apo C-II, apo C-III, and apo E did not change significantly. It is suggested that captopril monotherapy produces a favorable effect on HDL subfractions.     

Effects of a new calcium channel blocker, TA 3090, on serum lipoprotein levels in mild to moderate essential hypertension

The 25 hypertensive patients received 20 to 40 mg of TA 3090 daily for 12 weeks. Blood pressures declined significantly during treatment, from a mean of 162/98 to 145/88 mmHg. There were no significant changes in levels of total or very low-density lipoprotein cholesterol or triglyceride, in levels of low-density lipoprotein cholesterol, high-density lipoprotein (HDL) cholesterol, HDL2 cholesterol, HDL3 cholesterol, or in levels of apolipoprotein (apo) B, C-II, C-III, or E. Apo A-I and A-II levels increased significantly from 130 and 29.2 mg/dl before treatment to 152 and 31.4 mg/dl at 12 weeks. Mean serum creatinine levels decreased significantly from 0.92 to 0.80 mg/dl. No other drug-related changes in laboratory test results or side effects were noted. It is concluded that TA 3090 is a safe and effective treatment for mild to moderate hypertension.     

Abnormal high-density lipoprotein composition in women with insulin-dependent diabetes

To determine whether alterations in lipoprotein phospholipid composition might be an unrecognized factor that contributes to the unexplained acceleration of atherogenesis and the loss of sex-related protection from the development of coronary heart disease in women with insulin-dependent diabetes mellitus, we have estimated levels of neutral lipids, apolipoproteins (A-I, A-II, B), and free cholesterol (FC) in plasma and the four major phospholipid constituents of the very low-density lipoprotein + low-density lipoprotein and high-density lipoprotein (HDL) fractions in 12 ambulatory female patients with varying degrees of diabetic control. Although levels of triglyceride, cholesterol, HDL-cholesterol, and lipoprotein phospholipids in whole plasma of the patients with diabetes were similar to those in controls, their FC levels and FC/lecithin ratio, a recently described index of cardiovascular risk, both were abnormally increased (p less than 0.01). In the HDL-containing plasma fraction, concentrations of sphingomyelin, lecithin, and lysolecithin all were significantly reduced (p less than 0.05; p less than 0.01, and p less than 0.02, respectively). These compositional changes may be potentially atherogenic, because a reduction in the phospholipid content of HDL may impair its capacity to promote the efflux of cholesterol from cells, and the transfer of cholesterol ester from HDL to the larger apo-B-containing lipoproteins is inhibited when their content of FC is increased relative to phospholipid. These previously unrecognized qualitative defects, which are inapparent in the routine estimation of plasma lipids, may compromise reverse cholesterol transport and thereby promote atherogenesis in women with insulin-dependent diabetes mellitus.     

Hypertriglyceridemia and cholesteryl ester transfer protein interact to dramatically alter high density lipoprotein levels, particle sizes, and metabolism. Studies in transgenic mice.

Several types of transgenic mice were used to study the influence of hypertriglyceridemia and cholesteryl ester transfer protein (CETP) expression on high density lipoprotein (HDL) levels, particle sizes, and metabolism. The presence of the CETP transgene in hypertriglyceridemic human apo CIII transgenic mice lowered HDL-cholesterol (HDL-C) 48% and apolipoprotein (apo) A-I 40%, decreased HDL size (particle diameter from 9.8 to 8.8 nm), increased HDL cholesterol ester (CE) fractional catabolic rate (FCR) 65% with a small decrease in HDL CE transport rate (TR) and increased apo A-I FCR 15% and decreased apo A-I TR 29%. The presence of the CETP transgene in hypertriglyceridemic mice with human-like HDL, human apo A-I apo CIII transgenic mice, lowered HDL-C 61% and apo A-I 45%, caused a dramatic diminution of HDL particle size (particle diameters from 10.3 and 9.1 to 7.6 nm), increased HDL CE FCR by 107% without affecting HDL CE TR, and increased apo A-I FCR 35% and decreased apo A-I TR 48%. Moreover, unexpectedly, hypertriglyceridemia alone in the absence of CETP was also found to cause lower HDL-C and apo A-I levels primarily by decreasing TRs. Decreased apo A-I TR was confirmed by an in vivo labeling study and found to be associated with a decrease in intestinal but not hepatic apo A-I mRNA levels. In summary, the introduction of the human apo A-I, apo CIII, and CETP genes into transgenic mice produced a high-triglyceride, low-HDL-C lipoprotein phenotype. Human apo A-I gene overexpression caused a diminution of mouse apo A-I and a change from monodisperse to polydisperse HDL. Human apo CIII gene overexpression caused hypertriglyceridemia with a significant decrease in HDL-C and apo A-I levels primarily due to decreased HDL CE and apo A-I TR but without a profound change in HDL size. In the hypertriglyceridemic mice, human CETP gene expression further reduced HDL-C and apo A-I levels, primarily by increasing HDL CE and apo A-I FCR, while dramatically reducing HDL size. This study provides insights into the genes that may cause the high-triglyceride, low-HDL-C phenotype in humans and the metabolic mechanisms involved.     

Serum lipids and apolipoproteins A-I, A-II and B in primary hypothyroidism before and during treatment

Serum lipids and apolipoproteins (apo) A-I, A-II, and B were measured in twenty-four patients with severe primary hypothyroidism (Thyrotropin above 40 mU/l), before and during 1-thyroxine treatment. Apo A-I, A-II, and B were assayed by immunonephelometry, using monospecific antisera. The serum levels of total cholesterol (TC), of low-density lipoprotein cholesterol (LDLc), and of the major LDL apoprotein, apo B, were markedly increased in the untreated hypothyroid patients compared to the values during therapy (TC: mean +/- SD, 8.87 +/- 2.9 v. 5.48 +/- 1.6 mmol/l; LDLc: 6.66 +/- 2.6 v. 3.78 +/- 1.4 mmol/l; apo B: 1.66 +/- 0.48 v. 1.14 +/- 0.37 g/l; P less than 0.00001 for all variables). High-density lipoprotein cholesterol (HDLc) was slightly higher before than during therapy (1.58 +/- 0.7 v. 1.31 +/- 0.4 mmol/l; P less than 0.05), while the main HDL apoprotein, apo A-I, was significantly elevated (1.49 +/- 0.42 v. 1.13 +/- 0.27 g/l; P less than 0.0002). The increase of the second major HDL apoprotein, apo A-II, was less pronounced (0.33 +/- 0.1 v. 0.30 +/- 0.08 g/l; P less than 0.022). The apo A-I to apo A-II ratio, which reflects the relative concentrations of the HDL subfractions HDL2 and HDL3, was significantly higher before than during treatment (P less than 0.0006). Serum triglyceride levels were moderately elevated in the untreated hypothyroid patients (1.34 +/- 0.6 v. 0.95 +/- 0.4 mmol/l; P less than 0.002). The small decrease in body weight during therapy did not correlate with the changes of the various lipid and apoprotein parameters.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of replacing saturated fat with complex carbohydrate in diets of subjects with NIDDM

This study examined the safety of an isocaloric high-complex carbohydrate low-saturated fat diet (HICARB) in obese patients with non-insulin-dependent diabetes mellitus (NIDDM). Although hypocaloric diets should be recommended to these patients, many find compliance with this diet difficult; therefore, the safety of an isocaloric increase in dietary carbohydrate needs assessment. Lipoprotein cholesterol and triglyceride (TG, mg/dl) concentrations in isocaloric high-fat and HICARB diets were compared in 7 NIDDM subjects (fat 32 +/- 3%, fasting glucose 190 +/- 38 mg/dl) and 6 nondiabetic subjects (fat 33 +/- 5%). They ate a high-fat diet (43% carbohydrate; 42% fat, polyunsaturated to saturated 0.3; fiber 9 g/1000 kcal; cholesterol 550 mg/day) for 7-10 days. Control subjects (3 NIDDM, 3 nondiabetic) continued this diet for 5 wk. The 13 subjects changed to a HICARB diet (65% carbohydrate; 21% fat, polyunsaturated to saturated 1.2; fiber 18 g/1000 kcal; cholesterol 550 mg/day) for 5 wk. NIDDM subjects on the HICARB diet had decreased low-density lipoprotein cholesterol (LDL-chol) concentrations (107 vs. 82, P less than .001), but their high-density lipoprotein cholesterol (HDL-chol) concentrations, glucose, and body weight were unchanged. Changes in total plasma TG concentrations in NIDDM subjects were heterogeneous. Concentrations were either unchanged or had decreased in 5 and increased in 2 NIDDM subjects. Nondiabetic subjects on the HICARB diet had decreased LDL-chol (111 vs. 81, P less than .01) and unchanged HDL-chol and plasma TG concentrations).(ABSTRACT TRUNCATED AT 250 WORDS)     

Enhanced nitric oxide production is closely associated with serum lipid concentrations in adolescents

BACKGROUND: To investigate whether nitric oxide (NO) production is associated with serum lipid concentrations and body mass index (BMI), we measured serum nitrate and nitrites (NOx) concentrations, serum lipid profiles, and anthropometric parameters in 319 adolescents. METHODS: Serum NOx concentrations were determined using the Griess reaction. Serum concentrations of triglyceride, total cholesterol, and low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C) were measured by standard enzymatic procedures. RESULTS: Subjects with increased serum cholesterol or triglyceride concentrations exhibited remarkably high NOx levels. Total cholesterol and triglyceride averaged 161.5+/-27.4 and 205.9+/-107.8 mg/dl in males with NOx >92.8 micromol/l (upper 20%), which were significantly above the values (132.4+/-17.2 and 58.1+/-20.3 mg/dl) in those with NOx <15.6 micromol/l (lower 20%). The prevalences of male adolescents with increased concentrations of cholesterol and triglyceride were significantly higher in the subjects with NOx > or =51.2 micromol/l than in those with NOx <51.2 micromol/l (8.9% and 22.2% vs. 1.6% and 2.3%, p<0.05, respectively). Correlation coefficients of serum lipid concentrations and anthropometric parameters vs. serum NOx concentrations were higher in males than in females for cholesterol (r=0.28 vs. 0.23), triglyceride (r=0.51 vs. 0.42), HDL-C (r=-0.25 vs. -0.16), and BMI (r=0.39 vs. 0.27). CONCLUSIONS: NO production is closely associated with serum lipid concentrations in adolescents, and these associations are stronger in males than in females.     

HDL and clinical and biochemical correlates in Italian non-smoker women.

High-density lipoprotein (HDL)-cholesterol levels, inversely related to the risk of myocardial infarction, are determined by genetic and environmental factors. The aim of this study was to evaluate the prevalence of low and high HDL plasma levels and the influence of environmental factors and lipid profile in an Italian non-smoker female population. HDL, apolipoprotein A-I, apolipoproteins, lipids and estrogen plasma levels were measured in a population of 1471 women with a mean age of 45 +/- 14 years. HDL values < or = 35 mg/dl were noted in 11.2% of the subjects, showing 2.4% coronary heart disease (CHD) prevalence. The 90th percentile was characterized by HDL levels > or = 66 mg/dl and the absence of coronary atherosclerosis. Total cholesterol, apolipoprotein B and triglycerides (r = -0.31, p < 0.0001) were the main determinants of HDL levels; apolipoprotein E, estrogen use, body mass index (BMI), alcohol consumption and age showed a weaker correlation. Apolipoprotein A-I concentration was influenced more notably by estrogen use, total cholesterol and apolipoprotein E; levels of triglycerides, apolipoprotein B, BMI, age and alcohol consumption are less important. The parameters considered here, taken together, explain HDL and apolipoprotein A-I variability of approximately 31% and 24%, respectively. A surprisingly high prevalence of very low (< or = 35 mg/dl) and high (> or = 66 mg/dl) HDL levels in Italian women further confirms the importance of studies on the HDL distribution in different population groups.     

Very small apolipoprotein A-I-containing particles from human plasma: isolation and quantification by high-performance size-exclusion chromatography

BACKGROUND: Very small apolipoprotein (apo) A-I-containing lipoprotein (Sm LpA-I) particles with pre-beta electrophoretic mobility may play key roles as "nascent" and/or "senescent" HDL; however, methods for their isolation are difficult and often semiquantitative. METHODS: We developed a preparative method for separating Sm LpA-I particles from human plasma by high-performance size-exclusion chromatography (HP-SEC), using two gel permeation columns (Superdex 200 and Superdex 75) in series and measuring apo A-I content in column fractions in 30 subjects with HDL-cholesterol (HDL-C) concentrations of 0.4-3.83 mmol/L. RESULTS: Three major sizes of apo A-I-containing particles were detected: an approximately 15-nm diameter ( approximately 700 kDa) species; a 7. 5-12 nm (100-450 kDa) species; and a 5.8-6.3 nm species (40-60 kDa, Sm LpA-I particles), containing 0.2-3%, 80-96%, and 2-15% of plasma total apo A-I, respectively. Two subjects with severe HDL deficiency had increased relative apo A-I content in Sm LpA-I: 25% and 37%, respectively. The percentage of apo A-I in Sm LpA-I correlated positively with fasting plasma triglyceride concentrations (r = 0. 581; P <0.0005) and inversely with total apo A-I (r = -0.551; P <0. 0013) and HDL-C concentrations (r = -0.532; P <0.0017), although the latter two relationships were largely attributable to extremely hypoalphalipoproteinemic subjects. The percentage of apo A-I in Sm LpA-I correlated with that in pre-beta-migrating species by crossed immunoelectrophoresis (r = 0.98; P <0.0001; n = 24) and with that in the d >1.21 kg/L fraction by ultracentrifugation (r = 0.86; P <0. 001; n = 20). Sm LpA-I particles, on average, appear to contain two apo A-I and four phospholipid molecules but little or no apo A-II, triglyceride, or cholesterol. CONCLUSIONS: We present a new HP-SEC method for size separation of native HDL particles from plasma, including Sm Lp A-I, which may play important roles in the metabolism of HDL and in its contribution(s) to protection against atherosclerosis. This method provides a basis for further studies of the structure and function of Sm Lp A-I.     

Lipids and apolipoproteins in patients treated with major tranquilizers

The concentrations of lipids and apolipoproteins in serum from men with chronic schizophrenia who were receiving major tranquilizers (17 receiving phenothiazines and 14 receiving a butyrophenone) were quantitated and compared with serum from male controls (n = 14). Concentrations of high-density lipoprotein cholesterol and apolipoproteins A-I and A-II were significantly lower in the patients than in the controls. Mean apolipoproteins C-II and C-III and very low-density lipoprotein cholesterol levels in the patients receiving phenothiazines were higher than levels in the patients receiving butyrophenone or in the controls. There were no significant differences in levels of total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, or apolipoproteins B and E. The triglyceride level in patients receiving phenothiazines (163 +/- 65 mg/dl) was higher than that in patients receiving butyrophenone (104 +/- 52 mg/dl). Our data suggest that, with respect to triglyceride metabolism, butyrophenone is more beneficial than are phenothiazines.     

Lipoprotein physiology in nondiabetic and diabetic states. Relationship to atherogenesis

Abnormalities of plasma lipid and lipoprotein concentrations are common in both insulin-dependent (IDDM) and non-insulin-dependent (NIDDM) diabetes mellitus. In general, individuals with IDDM who are untreated or inadequately treated have elevations in both postprandial and fasting triglyceride levels in association with reduced activity of lipoprotein lipase. Low-density lipoprotein (LDL) cholesterol levels can rise when insulin deficiency impacts on LDL-receptor function. When patients with IDDM are treated and plasma glucose levels well controlled, plasma very-low-density lipoprotein (VLDL) triglyceride and LDL cholesterol levels are usually normal. In addition, plasma high-density lipoprotein (HDL) cholesterol levels are normal or elevated in well-controlled IDDM subjects. In NIDDM, increased VLDL triglyceride and reduced HDL cholesterol concentrations are common and are only partially related to glycemic control. Overproduction of VLDL leads to hypertriglyceridemia, which can be exacerbated if lipoprotein lipase activity is also reduced. The regulation of LDL levels is complex; catabolism can be reduced if significant insulin deficiency exists or increased if significant hypertriglyceridemia is present. The reduced levels of HDL cholesterol in NIDDM appear to be related to increased exchange of HDL cholesteryl esters for VLDL triglycerides, although other mechanisms may exist. The roles of insulin resistance, obesity, and independently inherited abnormalities of lipoprotein metabolism in the etiology of dyslipidemia of NIDDM are complex and require further investigation. Finally, the effects of diabetes on glycosylation of apoproteins; on other lipid enzymes, particularly hepatic triglyceride lipase; on lipoprotein surface lipids; and on hepatic uptake of remnants have only just begun to be defined. In view of the marked increase in atherosclerotic cardiovascular disease in individuals with diabetes mellitus, prompt attention to and aggressive therapy for dyslipidemia should be a central component of care for these patients.     

Low-dose, time-release nicotinic acid: effects in selected patients with low concentrations of high-density lipoprotein cholesterol.

In a retrospective analysis, 63 participants in a cardiac rehabilitation-preventive cardiology program were identified as having low blood concentrations (mean, 34 mg/dl) of high-density lipoprotein cholesterol (HDL-C) and a mean total cholesterol level of 223 mg/dl after 3 months of hygienic measures (aerobic exercise, avoidance of tobacco, diet, and weight loss) designed to increase the HDL-C level. These patients (treatment group) were treated with low-dose, time-release nicotinic acid (mean, 1,297 mg/day) for a mean duration of 7.4 months. All subjects were able to take the drug without intolerable side effects. Fifty-four patients similar to those in the treatment group participated in the same program but were not treated with nicotinic acid (control group). Exercise, diet, body weight, and smoking remained stable throughout the period of observation. For the treatment group, HDL-C levels increased a mean of 18% (+6 mg/dl), total cholesterol concentrations decreased 9% (-20 mg/dl), the ratio of total cholesterol to HDL-C decreased 25% (from 6.8 to 5.1), low-density lipoprotein cholesterol levels decreased 13% (-20 mg/dl), and triglyceride levels decreased 20% (from 165 mg/dl to 132 mg/dl). Aspartate aminotransferase and uric acid concentrations were minimally increased after treatment, and the blood glucose level was unchanged. In the control group, HDL-C levels increased a mean of 8% (+3 mg/dl) and the other blood lipid variables were not improved after a mean of 8.3 additional months of diet and exercise.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of pindolol on serum lipoproteins and postheparin lipolytic activities in hypertensive patients

Thirty-four hyperlipoproteinemic, hypertensive patients received 5 mg of pindolol twice daily for 12 weeks. During pindolol administration, there were significant decreases in serum triglyceride levels and increases in high-density lipoprotein cholesterol (HDL-C) levels, while total cholesterol levels did not change. Serum levels of very-low-density lipoprotein (VLDL) triglyceride and VLDL cholesterol decreased over time as HDL-C increased. There was a significant increase in low-density lipoprotein cholesterol at week 12. Apolipoprotein (apo) A-I, A-II, and B levels did not change during pindolol administration, but apo C-II, C-III, and E levels decreased significantly. Lipoprotein lipase activity in heparin-treated plasma was significantly higher after pindolol administration. The results suggest that the reduction in triglyceride levels and increase in HDL-C after pindolol are partly a response to an increase in the hydrolysis of VLDL resulting from an increase in lipoprotein lipase activity.