The effect of etophylline clofibrate on HDL subfractions

The effect of etophylline clofibrate on lipids and apolipoproteins of the high density lipoprotein (HDL) subfractions HDL2 and HDL3 as well as on very low density (VLDL) and low density lipoproteins (LDL) and the post heparin lipolytic activities (PHLA) of lipoprotein lipase (LPL) and hepatic triglyceride lipase (HTGL) has been studied in 14 patients with type II hyperlipoproteinemia (HLP). The study was preceded by a 4-week washout phase, followed by a 6-week placebo period. During the next 12 weeks, the patients received 750 mg etophylline clofibrate per day. Then the drug was again replaced by placebo for another 6 weeks. During the study the patients were on a low fat diet poor in cholesterol with a P/S ratio over 1.0. HDL cholesterol and apoproteins increased significantly during treatment. In the first verum phase this effect was related to the rise in HDL2 components with minor changes in HDL3 concentrations, whereas in the second verum period a distinct increase of the HDL3 components could be detected. This development was accompanied by a significant increase of the LPL activities during the first 6 weeks of treatment, followed by a decrease to initially measured values after 12 weeks. The drug lowered plasma- and LDL-cholesterol levels by 19% and 22%, and plasma and VLDL triglycerides by 22% and 25%, respectively. VLDL-C apoproteins (C-I, C-II, C-III) declined by 31% with a percentage increase of apo C-II compared with apo C-I and apo C-III.     

Effects of insulin on hypercholesterolemia in the streptozotocin-induced diabetic rats fed a high cholesterol diet

The effect of dietary cholesterol (Ch) on plasma lipoprotein and apolipoproteins (apo) in diabetic rats was investigated. Ch-fed diabetic rats were severely hypercholesterolemic and hypertriglyceridemic. They had higher concentrations of very low density lipoprotein (VLDL), intermediate density lipoprotein (IDL) and low density lipoprotein (LDL). Concentration of high density lipoprotein (HDL) was decreased. beta-VLDL increased predominantly in Ch-fed diabetic rats, whereas IDL increased in the Ch and propylthiouracil-fed control rats. According to sodium dodecyl sulfate polyacrylamide gel electrophoresis, VLDL and IDL from Ch-fed diabetic rats were unusual in that they contained more apo E, A-I and A-IV. Concentrations of plasma apo A-I and apo E were measured by radioimmunoassay. The diabetic rats fed a labo chow showed a significantly lower concentration of plasma apo E than control rats. Plasma apo E was extremely higher in the diabetic rats fed a cholesterol diet. Plasma apo A-I was significantly increased in the diabetic rats fed a labo chow and those fed a cholesterol. Insulin treatment significantly decreased the concentrations of VLDL, IDL and LDL and plasma concentration and distribution of apolipoproteins in lipoprotein subfractions changed toward normal. However, decreased HDL in the Ch-fed diabetic rats was not recovered by insulin treatment.     

Metabolic effects of a biphasic oral contraceptive preparation containing ethinyloestradiol and desogestrel on serum lipoproteins and apolipoproteins

The effect of the administration of a biphasic oral contraceptive containing ethinyloestradiol and desogestrel on the distribution and composition of serum lipoproteins was studied in a group of 17 healthy female volunteers. The women were treated for a period of 6 months and compared with a control group of ten untreated volunteers. The serum lipoproteins were fractionated by density gradient ultracentrifugation into very low density lipoproteins (VLDL), low density lipoproteins (LDL), and into the high density lipoprotein (HDL) subfractions 2 and 3 (HDL2, HDL3). Lipids and apolipoproteins were assayed in the various fractions. No modification of either the lipid or apolipoprotein concentrations was observed in the control group. In the treated group, sex hormone-binding globulin (SHBG) and cortisol-binding globulin (CBG), and the serum content of cholesterol, triglycerides, HDL-cholesterol, apolipoprotein A-I (apo A-I) and apolipoprotein A-II (apo A-II) increased significantly after 3 and 6 months. The cholesterol and apolipoprotein B (apo B) content of VLDL increased significantly after 3 and 6 months, but remained unchanged in LDL. High density lipoprotein subfraction 2 (HDL2)-cholesterol was significantly increased after 3 and 6 months but apo A-I only after 6 months. Since apo A-II did not change, the apo A-I/A-II ratio increased significantly after 6 months of treatment. In the HDL3 fraction, the apo A-I increase was significant after 3 and 6 months, while the increase of apo A-II was significant after 6 months. The apo A-I/A-II ratio remained constant.(ABSTRACT TRUNCATED AT 250 WORDS)     

Diverging effects of cholestyramine on apolipoprotein B and lipoprotein Lp(a). A dose-response study of the effects of cholestyramine in hypercholesterolaemia

Nineteen hypercholesterolaemic patients were randomly treated with either 16 or 8 g cholestyramine with a changeover after 6 weeks for a second 6-week period. During a third consecutive 6-week period all patients received 4 g cholestyramine daily. The low density lipoprotein (LDL) cholesterol and triglyceride concentrations decreased significantly (- 11%, - 21% and - 26% for LDL cholesterol on 4, 8 and 16 g, respectively) with a dose-response effect. However, the increase from 8 g to 16 g only caused a modest additional reduction of the lipid levels. The serum concentration of apolipoprotein (apo) B was correlated to the LDL cholesterol and decreased similarly in a dose-response fashion. However, the average reduction of apo B was less pronounced (- 4%, - 13% and - 17% on 4, 8 and 16 g of cholestyramine, respectively) resulting in a significant change of the apo B/LDL cholesterol ratio during treatment. There was a significant increase of the high density lipoprotein (HDL) cholesterol concentration, which was similar at all dose levels. Also, the apo A-I concentration in serum increased significantly but the relative decrease was less pronounced than that of HDL cholesterol, causing a significant decrease of the apo A-I/HDL cholesterol ratio. The apo A-II concentration in serum was unchanged or slightly decreased and the apo A-I/apo A-II ratio increased significantly.     

内源性高甘油三酯血症患者血浆极低密度脂蛋白、低密度脂蛋白及高密度脂蛋白对血凝及纤维蛋白溶解的影响

研究内源性高甘油三酯血症患者血浆极低密度脂蛋白、低密度脂蛋白及高密度脂蛋白是否发生了氧化修饰及其对凝血及纤维蛋白溶解活性的影响。对 2 1例内源性高甘油三酯血症患者与 2 1例年龄性别相近的正常人的血脂、脂质过氧化物进行了分析。用一次性密度梯度超速离心法分离血浆极低密度脂蛋白、低密度脂蛋白及高密度脂蛋白。测定这 3种脂蛋白的 2 34nm吸光度、相对电泳迁移率和硫代巴比妥酸反应物质含量。分别将这 3种脂蛋白加入由正常人新鲜混合血浆构成的反应系统中 ,按试剂盒分别测定凝血酶原时间、活化部分凝血酶原时间、组织型纤溶酶原激活物活性及纤溶酶原激活物抑制剂 1活性。内源性高甘油三酯血症患者血浆甘油三酯含量平均升高 2 .73倍 ,高密度脂蛋白胆固醇下降 1.71倍 ,同时硫代巴比妥酸反应物质含量升高 1.2 2倍 ;内源性高甘油三酯血症组极低密度脂蛋白、低密度脂蛋白及高密度脂蛋白的 2 34nm吸光度、相对电泳迁移率和硫代巴比妥酸反应物质含量均较对照组显著增加 (P <0 .0 1) ,表明内源性高甘油三酯血症患者血浆极低密度脂蛋白、低密度脂蛋白及高密度脂蛋白均发生了氧化修饰 ,生成了氧化极低密度脂蛋白、氧化低密度脂蛋白及氧化高密度脂蛋白。凝血酶原时间及活化部分凝血酶原时间在分别加入内     

Effects of unopposed conjugated equine estrogen on lipoprotein composition and apolipoprotein-E distribution.

Administration of conjugated equine estrogen to 31 postmenopausal women for 3 months produced 14.6% and 9.4% decreases in low density lipoprotein cholesterol (LDL-C) and apolipoprotein-B (apoB), and 11.5%, 12.7%, and 9.6% increases in high density lipoprotein cholesterol (HDL-C), apoA-I and apoA-II, respectively. Phospholipids of HDL2 and HDL3 were increased 57.9% and 19.3%, respectively, while relatively small increases in cholesterol of the two subfractions were not significant. Compositions of LDL and HDL and its subfractions were altered substantially with estrogen treatment. The proportion of LDL triglyceride to LDL-C was increased. The phospholipid content in both the HDL2 and HDL3 subfractions (compared to cholesterol) was increased significantly (34.8% and 10.7%, respectively), while the triglyceride content was increased only in the HDL2 subfraction (43.6%). Estrogen use also caused a 9.1% reduction in total apoE levels and a redistribution of apoE to the very low density lipoprotein (VLDL) from the LDL plus HDL fraction, resulting in a significant 19.5% decrease in apoE in the LDL plus HDL fraction. Changes in apoE in the VLDL fraction were associated positively with changes in the cholesterol levels of the VLDL fraction and inversely with changes in LDL-C and apoB levels, while changes in apoE in the LDL plus HDL fraction were associated positively with changes in the levels of HDL-C. Thus, estrogen causes alterations in lipoproteins that could potentially affect their metabolism and/or function.     

The effect of high dose atorvastatin therapy on lipids and lipoprotein subfractions in overweight patients with type 2 diabetes

Few data are available on the effects of high dose statin therapy on lipoprotein subfractions in type 2 diabetes. In a double blind randomised placebo-controlled trial we have studied the effects of 80 mg atorvastatin over 8 weeks on LDL, VLDL and HDL subfractions in 40 overweight type 2 diabetes patients. VLDL and LDL subfractions were prepared by density gradient ultracentrifugation. Triglycerides, cholesterol, total protein and phospholipids were measured and mass of subfractions calculated. HDL subfractions were prepared by precipitation. Atorvastatin 80 mg produced significant falls in LDL subfractions (LDL(1) 66.2 mg/dl:36.6 mg/dl, LDL(2) 118:56.6 mg/dl, LDL(3) 36.9:19.9 mg/dl all P < 0.01 relative to placebo) and VLDL subfractions (VLDL(1) 55:22.1 mg/dl, VLDL(2) 40.1:19.1 mg/dl, VLDL(3) 52.6:30 mg/dl all P < 0.01 relative to placebo). There was no change in the proportion of LDL present as LDL(3). There was a reduction in the proportion of VLDL as VLDL(1) and a reciprocal increase in the proportion as VLDL(3). Changes in VLDL subfractions were associated with changes in lipid composition, particularly a reduction in cholesterol ester and a reduction in the cholesterol ester/triglyceride ratio. Effects on HDL subfractions were largely neutral. High dose atorvastatin produces favourable effects on lipoprotein subfractions in type 2 diabetes which may enhance antiatherogenic potential.     

Hyperthyroidism influences the distribution and apolipoprotein A composition of the high density lipoproteins in man

Hyperthyroidism has a different influence on the major high density lipoprotein (HDL) components cholesterol, apoprotein (apo) A-I, and apo A-II. To characterize in greater detail the alterations induced by hyperthyroidism within the HDL subclasses, we investigated HDL distribution and composition in 11 hyperthyroid women before and during treatment. The plasma concentrations of total cholesterol, HDL cholesterol, phospholipids, apo A-I, and apo B were decreased when the patients were hyperthyroid compared with the values during treatment. Apo A-II and apo C-III levels were only slightly lower in the hyperthyroid state. Triglyceride and apo E concentrations did not change significantly during therapy. Analysis of lipoprotein subclasses separated by isopycnic ultracentrifugation revealed 1) marked decreases in low density lipoprotein (LDL) cholesterol, phospholipids, and apo B; 2) less pronounced reductions in the very low density lipoprotein (VLDL) lipid and apo B concentrations; and 3) a consistent decrease in the HDL2b (density, 1.063-1.100 g/ml) fraction in the hyperthyroid patients. The reduction in HDL2b mass was associated with lower concentrations of HDL2b cholesterol, phospholipids, and apo A-I. The HDL2b apo A-II levels remained constant during treatment. Hyperthyroidism, therefore, modified the apo A composition of the HDL2b particles and resulted in a decreased molar apo A-I to apo A-II ratio within HDL2b. Further analysis of HDL particles differing in their apo A composition; i.e. HDL particles containing apo A-I only [(A-I)HDL] or containing both apo A-I and A-II [(A-I + A-II)HDL], by immunological procedures suggested that hyperthyroidism influenced the apo A content of HDL2b mainly by changing the proportions of (A-I)HDL and (A-I + A-II)HDL and the amount of apo A-I associated with (A-I)HDL. Treatment reversed the preferential decrease in (A-I)HDL within the HDL2b subclass. The particle sizes within HDL subfractions, measured by polyacrylamide gradient gel electrophoresis, were similar in the untreated and treated patients. Consequently, the decreased mass of apo A-I and lipids within HDL2b in the hyperthyroid patients could be attributed to a reduced number of identically sized particles within this fraction. These data demonstrate that the thyroid hormones are important regulators of HDL metabolism through their influence on the concentration and distribution of apo A-I.     

Effect of postpartum lactation on lipoprotein lipids and apoproteins

To determine if postpartum lactation alters plasma lipoprotein lipid and apoprotein concentrations and composition, we studied 56 overnight fasting lactating and 16 nonlactating women approximately 6 weeks postpartum. Postpartum results are presented as absolute concentrations and as the difference from antepartum values determined at 36 weeks gestation. Antepartum lipoprotein lipid and apoprotein concentrations were generally not different in the 2 groups, with the single exception of whole plasma and low density lipoprotein (LDL) apoprotein (apo) B (probably a chance difference). When expressed as the antepartum and postpartum difference, the lactating and nonlactating groups were indistinguishable in very low density lipoprotein (VLDL) and LDL triglyceride, cholesterol, phospholipid, and apo B concentrations. However, lactating women had higher high density lipoprotein (HDL) cholesterol, phospholipid, apo A-I, and apo A-II concentrations than nonlactating women when results were expressed as differences from antepartum values or as absolute values. HDL triglyceride concentrations were not significantly different between lactating and nonlactating women by either analysis. There was no significant effect of lactation on VLDL or LDL composition, but there was a significant increase in the percent cholesterol content in HDL. We hypothesize that the increase in HDL constituents in lactation is generated in part by increased catabolism of triglyceride-rich lipoproteins by the lactating breast.     

Changes in the composition of plasma lipoproteins in the chronic uremic rat

The effect of chronic renal failure on the lipid and apolipoprotein concentrations of plasma, very low density lipoproteins (VLDL), intermediate density lipoproteins (IDL), low density lipoproteins (LDL) and high density lipoproteins (HDL) was studied in an experimental uremic rat model. Control rats were sham-operated and were divided into adlibitum-fed and pair-fed groups. The rats were studied (after an overnight fast) 32 days after the onset of uremia. The uremic rats had a 4-fold increase in plasma urea nitrogen and creatinine. The pair-fed and ad-lib-fed controls had similar levels of plasma urea nitrogen and lipid profiles. In the uremic rats, plasma triglyceride (TG) levels were increased 3.8-fold due to increased TG in the VLDL, IDL and HDL fractions. Their 2-3-fold increase in plasma free cholesterol (FC), esterified cholesterol (EC) and phospholipids (PL) were due to FC, EC and PL increases in VLDL, IDL, LDL and HDL. Their increase in plasma apo B (x 2.4) and apo E (x 1.5) were due to increases in VLDL, IDL and LDL. Their plasma apo A-I increased 2.4 fold due to increases in the LDL and HDL fractions. Uremic rats also had increases in the FC/PL molar ratio in VLDL, IDL and LDL. In their LDL, the apo B/total cholesterol (TC), apo B/PL and apo B/apo E molar ratios were decreased. In their HDL, the apo E/TC and apo E/PL molar ratios were decreased and the apo A-I/apo E molar ratio was increased. In conclusion, chronic uremia causes both quantitative changes in the levels and qualitative changes in the composition of the plasma lipoprotein particles. These results are compatible with the decreased hepatic lipase activities and impairment of remnant clearance observed in human chronic renal failure.     

Differential effect of fenofibrate and atorvastatin on in vivo kinetics of apolipoproteins B-100 and B-48 in subjects with type 2 diabetes mellitus with marked hypertriglyceridemia

The specific impact of 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors and fibrates on the in vivo metabolism of apolipoprotein (apo) B has not been systematically investigated in patients with type 2 diabetes mellitus with high plasma triglyceride (TG) levels. Therefore, the objective of this 2-group parallel study was to examine the differential effects of a 6-week treatment with atorvastatin or fenofibrate on in vivo kinetics of apo B-48 and B-100 in men with type 2 diabetes mellitus with marked hypertriglyceridemia. Apolipoprotein B kinetics were assessed at baseline and at the end of the intervention using a primed constant infusion of [5,5,5-D(3)]-l-leucine for 12 hours in the fed state. Fenofibrate significantly decreased plasma TG levels with no significant change in plasma low-density lipoprotein cholesterol (LDL-C) and apo B levels. On the other hand, atorvastatin significantly reduced plasma levels of TG, LDL-C, and apo B. After treatment with fenofibrate, very low-density lipoprotein (VLDL) apo B-100 pool size (PS) was decreased because of an increase in the fractional catabolic rate (FCR) of VLDL apo B-100. No significant change was observed in the kinetics of LDL apo B-100. Moreover, fenofibrate significantly decreased TG-rich lipoprotein (TRL) apo B-48 PS because of a significant increase in TRL apo B-48 FCR. After treatment with atorvastatin, VLDL and IDL apo B-100 PSs were significantly decreased because of significant elevations in the FCR of these subfractions. Low-density lipoprotein apo B-100 PS was significantly lowered because of a tendency toward decreased LDL apo B-100 production rate (PR). Finally, atorvastatin reduced TRL apo B-48 PS because of a significant decrease in the PR of this subfraction. These results indicate that fenofibrate increases TRL apo B-48 as well as VLDL apo B-100 clearance in men with type 2 diabetes mellitus with marked hypertriglyceridemia, whereas atorvastatin increases both VLDL and IDL apo B-100 clearance and decreases TRL apo B-48 and LDL apo B-100 PR.     

Regional adiposity patterns in relation to lipids, lipoprotein cholesterol, and lipoprotein subfraction mass in men

Anatomical adipose tissue distribution patterns are reported to relate to plasma lipids and risk of cardiovascular disease. Waist to hip girth ratios (WHR) and subscapular 10 triceps skinfold thickness ratios (STR) were compared with percent body fat and body mass index values as correlates of plasma lipids and lipoprotein cholesterol and serum lipoprotein subfraction mass by analytic ultracentrifugation in 81 sedentary middle-aged men in a typical range of adiposity. WHR was significantly and positively correlated with plasma concentrations of triglycerides, cholesterol, and low and very low density lipoprotein (LDL and VLDL) cholesterol and inversely correlated with high density lipoprotein (HDL) cholesterol. STR followed these trends, though less strongly, in relation to plasma triglycerides, VLDL cholesterol, and HDL cholesterol. Pronounced differences were found between regional adiposity patterns in their relationships to lipoprotein subfractions, as determined by analytic ultracentrifugation. WHR was negatively correlated with HDL2 (flotation rate F(1.2) 3.5-9), positively with small LDL (S.f 0-7), intermediate density lipoprotein (S.f 12-20), and VLDL (S.f 20-400), while STR correlated with larger LDL (S.f 7-12) and larger VLDL (S.f 60-400). Overall adiposity was not significantly associated with plasma lipoprotein levels after adjusting for regional adiposity patterns. Plasma sex hormone-binding globulin and percent free testosterone were associated with regional adiposity, but did not account for the correlations between WHR and lipoproteins. WHR and STR are measures of fat distribution that correlate with plasma lipoprotein profiles consistent with cardiovascular disease risk and have different relationships to lipoprotein mass subfractions.     

Lipid and apoprotein modifications in body builders during and after self-administration of anabolic steroids

To determine the effects of anabolic steroids on serum lipid and apoprotein levels, 14 white male body builders who self-administered steroids for 2 to 3 months (steroid users) were studied; 10 agreed to screening while they were taking the drugs (ON treatment) and also at about 3 months following their suspension (OFF treatment). Controls consisted of 17 body builders who had never taken steroids (nonusers), and a group of 18 healthy sedentary subjects (controls). During the period of steroid administration, there was a slight reduction in total serum cholesterol, with a marked cholesterol decrease in the high-density lipoprotein (HDL) subfractions HDL2 and HDL3, and a significant reduction in the HDL2 cholesterol/HDL3 cholesterol ratio; the percentage of serum cholesterol transported by low-density lipoproteins (LDL) increased significantly. In addition, a marked apoprotein (apo) A-I reduction in the HDL2 and HDL3 subfractions was observed, as well as an apo A-II decrease that was significant only in the HDL3 subfraction, with an A-I/A-II ratio significantly reduced in both subfractions. Serum apo B was only slightly increased, with a very high B/A-I ratio. Apolipoprotein C-II and E levels showed no modifications, while apo C-III reduced significantly. Lipid and apoprotein values returned to almost normal levels in the OFF treatment period. Findings in the group of nonusers were similar to those in sedentary subjects. These results indicate that anabolic steroids profoundly alter the serum lipid-protein profile, and the changes may be caused in part by the significant differences observed in apoprotein levels.     

Apolipoprotein E polymorphism in men and women from a Spanish population: allele frequencies and influence on plasma lipids and apolipoproteins.

The apolipoprotein (apo) E phenotype and its influence on plasma lipid and apolipoprotein levels were determined in men and women from a working population of Madrid, Spain. The relative frequencies of alleles epsilon(2), epsilon(3) and epsilon(4) for the study population (n=614) were 0.080, 0.842 and 0.078, respectively. In men, apo E polymorphism was associated with variations in plasma triglyceride and very low-density lipoprotein (VLDL) lipid levels. It was associated with the proportion of apo C-II in VLDL, and explained 5.5% of the variability in the latter parameter. In women apo E polymorphism was associated with the concentrations of plasma cholesterol and low-density lipoprotein (LDL) and high-density lipoprotein (HDL) related variables. The allelic effects were examined taking allele epsilon(3) homozygosity as reference. In men, allele epsilon(2) significantly increased VLDL triglyceride and VLDL cholesterol concentrations, and this was accompanied by an increase of the apo C-II content in these particles. Allele epsilon(4) did not show any significant influence on men's lipoproteins. In women, allele epsilon(2) lowered LDL cholesterol and apo B levels, while allele epsilon(4) increased LDL cholesterol and decreased the concentrations of HDL cholesterol, HDL phospholipid and apo A-I. These effects were essentially maintained after excluding postmenopausal women and oral contraceptive users from the analysis. In conclusion: (1) the population of Madrid, similar to other Mediterranean populations, exhibits an underexpression of apo E4 compared to the average prevalence in Caucasians, (2) gender interacts with the effects of apo E polymorphism: in women, it influenced LDL and HDL levels, whereas in men it preferentially affected VLDL, and (3) allele epsilon(2) decreased LDL levels in women, while it increased both VLDL lipid levels and apo C-II content in men, but, in contrast to allele epsilon(4), it did not show an impact on HDL in either sex.     

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)     

Relationships of low density lipoprotein subfractions to angiographically defined coronary artery disease in young survivors of myocardial infarction.

Low density lipoprotein (LDL) from 36 young post-infarction patients was separated by isopycnic density gradient ultracentrifugation to determine the relationships of plasma levels and chemical composition of different LDL subfractions to the global severity and rate of progression of coronary atherosclerosis assessed by angiography. There were marked elevations of the cholesterol and triglyceride concentrations in the very low density lipoprotein (VLDL) fraction, whereas the high density lipoprotein (HDL) cholesterol level was reduced in the patients compared with 70 healthy population-based controls. Plasma total LDL cholesterol and triglyceride concentrations were similar. The distribution of apolipoprotein B along the LDL density range, viz. the LDL particle distribution, was displaced towards the dense LDL region among the patients compared with 14 healthy normolipidaemic controls. A preponderance of dense LDL particles was associated with elevated plasma VLDL triglyceride concentration. The patients had significantly higher plasma concentrations of lipid and protein in dense LDL (d greater than 1.040 kg/l), while no group differences were found in the light LDL (d less than 1.040 kg/l). However, there were no percentage compositional differences in the light or dense LDL between patients and controls. Among all constituents of lipoprotein fractions and subfractions determined, only the plasma level of triglycerides in both light and dense LDL correlated significantly with the angiographic estimates of global severity and rate of progression of coronary atherosclerosis, respectively. On a percentage composition basis, both light and dense LDL tended to be richer in triglycerides in the subjects with a more severe coronary artery disease. Neither VLDL or HDL, nor LDL cholesterol were associated with the angiographic scores, the plasma LDL triglyceride concentration or the triglyceride enrichment of LDL. Although there is ample experimental evidence that triglyceride-enriched LDL predisposes to atherosclerosis, the LDL associations with coronary lesion severity and progression observed in the present study might not reflect a causal mechanism, but merely mirror the atherogenicity of disturbances affecting the metabolism of triglyceride-rich lipoproteins. Prospective studies of larger groups of unselected patients are needed to corroborate these findings.     

Effects of atorvastatin on postprandial plasma lipoproteins in postinfarction patients with combined hyperlipidaemia

Enhanced and prolonged postprandial lipaemia is implicated in coronary and carotid artery disease. This study assessed the effects of atorvastatin, a 3-hydroxy-3-methylglutaryl-CoA reductase inhibitor, on postprandial plasma concentrations of triglyceride-rich lipoproteins (TRLs). Sixteen middle-aged men with combined hyperlipidaemia (baseline low density lipoprotein (LDL) cholesterol and plasma triglyceride concentrations (median (interquartile range) of 4.54 (4.17-5.26)) and 2.66 (2.04-3.20) mmol/l, respectively) and previous myocardial infarction were randomised to atorvastatin 40 mg or placebo once daily for 8 weeks in a double-blind, cross-over design. The apolipoprotein (apo) B-48 and B-100 contents were determined in subfractions of TRLs as a measure of chylomicron remnant and very low density lipoprotein (VLDL) particle concentrations (expressed as mg apo B-48 or apo B-100 per litre of plasma), in the fasting state and after intake of a mixed meal. Atorvastatin treatment reduced significantly the fasting plasma concentrations of VLDL cholesterol, LDL cholesterol and VLDL triglycerides (median% change) by 29, 44 and 27%, respectively, and increased high density lipoprotein (HDL) cholesterol by 19%, compared with baseline. The postprandial plasma concentrations of large (Svedberg flotation rate (Sf) 60-400) and small (Sf 20-60) VLDLs and chylomicron remnants were almost halved compared with baseline (mean 0-6 h plasma concentrations were reduced by 48% for Sf 60-400 apo B-100, by 46% for Sf 60-400 apo B-48, by 46% for Sf 20-60 apo B-100 and by 27% for Sf 20-60 apo B-48), and the postprandial triglyceridaemia was reduced by 23% during active treatment. In conclusion, atorvastatin 40 mg once daily causes profound reductions of postprandial plasma concentrations of all TRLs in combined hyperlipidaemic patients with premature coronary artery disease.     

Dose-dependent effect of rosuvastatin on apolipoprotein B-100 kinetics in the metabolic syndrome

In a randomized, double-blind, crossover trial of 5-week treatment period with placebo or rosuvastatin (10 or 40 mg/day) with 2-week placebo wash-outs between treatments, the dose-dependent effect of rosuvastatin on apolipoprotein (apo) B-100 kinetics in metabolic syndrome subjects were studied. Compared with placebo, there was a significant dose-dependent decrease with rosuvastatin in plasma cholesterol, triglycerides, LDL cholesterol, apoB and apoC-III concentrations and in the apoB/apoA-I ratio, lathosterol:cholesterol ratio, HDL cholesterol concentration and campesterol:cholesterol ratio also increased significantly. Rosuvastatin significantly increased the fractional catabolic rates (FCR) of very-low density lipoprotein (VLDL), intermediate density lipoprotein (IDL) and LDL-apoB and decreased the corresponding pool sizes, with evidence of a dose-related effect. LDL apoB production rate (PR) fell significantly with rosuvastatin 40 mg/day with no change in VLDL and IDL-apoB PR. Changes in triglycerides were significantly correlated with changes in VLDL apoB FCR and apoC-III concentration, and changes in lathosterol:cholesterol ratio were correlated with changes in LDL apoB FCR, the associations being more significant with the higher dose of rosuvastatin. In the metabolic syndrome, rosuvastatin decreases the plasma concentration of apoB-containing lipoproteins by a dose-dependent mechanism that increases their rates of catabolism. Higher dose rosuvastatin may also decrease LDL apoB production. The findings provide a dose-related mechanism for the benefits of rosuvastatin on cardiovascular disease in the metabolic syndrome.     

Alcohol dose and low density lipoprotein heterogeneity in squirrel monkeys (Saimiri sciureus).

The present study was designed to determine whether normolipidemic male squirrel monkeys (Saimiri sciureus) exhibit low density lipoprotein (LDL) heterogeneity similar to that observed in humans and if present, whether LDL subfractions are altered by consumption of low vs. high dose ethanol (EtOH). Primates were divided into three groups designated control, low, and high EtOH and fed isocaloric liquid diets containing 0%, 12% and 24% of calories as EtOH, respectively, for 6 months. The 12% EtOH caloric level resulted in a modest, non-significant increase in high density lipoprotein (HDL) cholesterol and no change in LDL cholesterol or plasma apolipoprotein B (apo B), while the 24% dose produced significant elevations in plasma, LDL and HDL cholesterol and apo B. Using a single-spin density gradient ultracentrifugation procedure developed for humans, three distinct LDL subclasses designated LDL1a (d = 1.031 g/ml), LDL1b (d = 1.038 g/ml) and LDL 2 (d = 1.046 g/ml) were isolated from all three treatment groups. Monkey LDL subfractions were nearly identical to very light, light and heavy LDL subspecies isolated from human plasma in terms of their: (1) isopycnic densities following ultracentrifugation; (2) co-migration as single bands with beta-electrophoretic mobility in cellulose acetate and agarose electrophoretic gels; (3) size-dependent migration pattern in polyacrylamide gradient electrophoretic gels; (4) co-migration as a single band corresponding to apo B-100, following SDS polyacrylamide gel electrophoresis; and (5) decrease in total cholesterol/protein ratios with increasing LDL subclass density. Although there were no treatment differences in LDL particle size, within each treatment group, mean particle size for each LDL subfraction was significantly different from every other subfraction. Low (12%) dose alcohol had no effect on LDL subfraction mass relative to controls while high alcohol consumption resulted in marked increases in all lipid (except triglyceride) and protein of the larger, buoyant LDL subspecies (LDL1a and LDL1b). Moreover, the best correlation between plasma apo B and LDL subfraction total mass was demonstrated with LDL1b (r = 0.735). Since neither the lipid nor the protein concentration of the small, dense, purportedly more atherogenic, LDL2 changed with the 24% EtOH dose, we propose that the LDL subfraction alterations associated with high alcohol intake in squirrel monkeys (increased LDL1a, increased LDL1b, LDL2 no effect) may represent a compensatory response to modulate the overall atherogenic lipoprotein profile associated with elevations in total LDL cholesterol and plasma apolipoprotein B.     

Influence of weight reduction on plasma high-density-lipoprotein cholesterol concentrations in severe obesity: interrelationships with plasma insulin levels.

The influence of caloric restriction and of weight loss during a weight-maintaining diet on lipid profile and in particular on high density lipoprotein (HDL) is controversial. In this study we analyzed the effect of a period of very low caloric diet (VLCD) and of a period of hypocaloric diet followed by 30 days of weight stabilization on lipoprotein levels, especially on HDL cholesterol and its subfractions (HDL2 and HDL3) and on the summated means of glucose (sigma glucose) and insulin levels (sigma IRI) after an oral tolerance test in a group of obese females. Body weight decreased significantly during the VLCD and hypocaloric diet. Total cholesterol decreased significantly after the VLCD and hypocaloric diet, but after the period of the weight-maintaining diet it was superimposable to the initial value. Very low density lipoprotein (VLDL) and low density lipoprotein (LDL) cholesterol behaved like total cholesterol. HDL2, HDL3 and HDL cholesterol decreased significantly after the period of VLCD. Then, after the hypocaloric diet the values of HDL2, HDL3 and HDL cholesterol returned towards the initial values and only after the period of the weight-maintaining diet did their values increase significantly. sigma glucose did not vary significantly at any time of the study, while sigma IRI reduced significantly both after the hypocaloric diet and the weight-maintaining diet. HDL2 and HDL cholesterol changes were found to be positively correlated to the variations of sigma IRI both at day 45 and 75 of the study.(ABSTRACT TRUNCATED AT 250 WORDS)