Increase In Serum Lipoproteins Research Articles

Lipoprotein(a) in the Korean Pediatric Population Visiting Local Clinics and Hospitals.

In this paper we investigate serum lipoprotein(a), an independent risk factor for cardiovascular disease in the Korean pediatric population. Visiting local clinics and hospitals, 600 lipoprotein(a) tests were performed on 416 Korean children and adolescents (124 boys and 292 girls), with a median age of 11.1 years (interquartile range, IQR, 9.8–13.9). The median lipoprotein(a) level was 21.5 nmol/L (IQR, 8.2–51.7). Among the 416 patients, the 90th percentile value of the initial lipoprotein(a) measurement was 107.8 nmol/L. The proportion of patients with lipoprotein(a) ≥ 100 nmol/L was 11.3%. The lipoprotein(a) level and the proportion of patients with lipoprotein(a) ≥ 100 nmol/L were not significantly different among sex, or age group. Among the 416 patients, 122 (29.3%, 21 boys and 101 girls) underwent at least two follow-up lipoprotein(a) measurements. The median follow-up period was 6.7 months (IQR, 5.5–11.8). The median lipoprotein(a) level across the 122 patients was 25 nmol/L (IQR 10.0–72.0). Among those patients, seven (5.7%) experienced an increase in serum lipoprotein(a) to ≥100 nmol/L during follow-up measurements. Further studies are needed in the Korean pediatric population in order to clarify the clinical significance of this change long-term.

Effect of conjugated estrogens and bazedoxifene on glucose, energy and lipid metabolism in obese postmenopausal women.

Combining conjugated estrogens (CE) with the selective estrogen receptor modulator bazedoxifene (BZA) is a novel, orally administered menopausal therapy. We investigated the effect of CE/BZA on insulin sensitivity, energy metabolism, and serum metabolome in postmenopausal women with obesity. Randomized, double-blind, crossover pilot trial with washout was conducted at Pennington Biomedical Research Center. Eight postmenopausal women (age 50-60 years, BMI 30-40 kg/m2) were randomized to 8 weeks CE/BZA or placebo. Primary outcome was insulin sensitivity (hyperinsulinemic-euglycemic clamp). Secondary outcomes included body composition (DXA); resting metabolic rate (RMR); substrate oxidation (indirect calorimetry); ectopic lipids (1H-MRS); fat cell size, adipose and skeletal muscle gene expression (biopsies); serum inflammatory markers; and serum metabolome (LC/MS). CE/BZA treatment produced no detectable effect on insulin sensitivity, body composition, ectopic fat, fat cell size, or substrate oxidation, but resulted in a non-significant increase in RMR (basal: P = 0.06; high-dose clamp: P = 0.08) compared to placebo. CE/BZA increased serum high-density lipoprotein (HDL)-cholesterol. CE/BZA also increased serum diacylglycerol (DAG) and triacylglycerol (TAG) species containing long-chain saturated, mono- and polyunsaturated fatty acids (FAs) and decreased long-chain acylcarnitines, possibly reflecting increased hepatic de novo FA synthesis and esterification into TAGs for export into very low-density lipoproteins, as well as decreased FA oxidation, respectively (P < 0.05). CE/BZA increased serum phosphatidylcholines, phosphatidylethanolamines, ceramides, and sphingomyelins, possibly reflecting the increase in serum lipoproteins (P < 0.05). A short treatment of obese postmenopausal women with CE/BZA does not alter insulin action or ectopic fat but increases serum markers of hepatic de novo lipogenesis and TAG production.

Correlation between anthropometric measurement, lipid profile, dietary vitamins, serum antioxidants, lipoprotein (a) and lipid peroxides in known cases of 345 elderly hypertensive South Asian aged 56–64 y–A hospital based study

To address the association of dietary vitamins, anthropometric profile, lipid profile, antioxidant enzymes and lipid peroxidation in hypertensive participant compared with normotensive healthy controls. Dietary intake of vitamins was assessed by 131 food frequency questionnaire items in both hypertensive participants and normotensive age-sex matched healthy controls. The associated changes in serum antioxidants and lipid peroxidation were also assessed along with lipid profile and anthropometric measurements in both groups of subjects under study. Dietary vitamins intake was higher in hypertensive participants excepting for vitamin B2 and ascorbic acid compared to normotensive controls. Anthropometric variables in the hypertensive showed significant differences in weight, body mass index, waist circumference, hip circumference, waist-hip ratio and mid-arm circumference. The total cholesterol, low-density lipoprotein cholesterol, triglyceride were significantly higher (P<0.001) in hypertensive except high-density lipoprotein cholesterol which was significantly higher (P<0.001) in normotensive. The serum endogenous antioxidants and enzyme antioxidants were significantly decreased in hypertensive except serum albumin levels compared to normotensive along with concomitant increase in serum lipoprotein (a) malondialdehyde and conjugated diene levels. Based on the observations, our study concludes that hypertension is caused due to interplay of several confounding factors namely anthropometry, lipid profile, depletion of endogenous antioxidants and rise in oxidative stress.

Early and persistent increase in serum lipoprotein (a) concentrations in epileptic children treated with carbamazepine and sodium valproate monotherapy

Purpose The aim of this study was to investigate by a prospective, self-controlled method, whether treatment with carbamazepine (CBZ) and sodium valproate (VPA) monotherapy may alter serum lipoprotein (a) [Lp(a)] concentrations in epileptic children. Methods Serum Lp(a) concentrations have been determined in 18 epileptic children before and at 6, 12 and 24 months of treatment with CBZ monotherapy and in 30 epileptic children before and at 6, 12 and 24 months of treatment with VPA monotherapy. Serum total cholesterol, triglycerides, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, apolipoproteins A-I and B concentrations and serum concentrations of biochemical markers of liver and renal function were also measured in the study participants. Results Serum Lp(a) concentrations were significantly increased at 6, 12 and 24 months of CBZ and VPA monotherapy. There were no significant correlations between serum Lp(a) and serum lipids, lipoproteins, apolipoproteins, concentrations of biochemical markers of liver and renal function or antiepileptic-drugs concentrations. Conclusions Children who receive CBZ or VPA monotherapy may have significant and persistent increase in serum lipoprotein (a) concentrations, occuring early in the course of therapy. It may be useful to measure serum Lp(a) concentrations routinely in epileptic children taking these antiepileptic drugs, especially in those that are already at higher atherosclerotic risk.

Lipoprotein(a) enhances the expression of intercellular adhesion molecule-1 in cultured human umbilical vein endothelial cells.

We reported an increase in serum lipoprotein(a) [Lp(a)] levels in patients with thromboangiitis obliterans, suggesting that Lp(a) could also contribute to the pathogenesis of cardiovascular diseases by a mechanism different from atherosclerosis. Adhesion molecules were shown to contribute to the development of not only atherosclerotic but also inflammatory vascular diseases. We evaluated the effect of Lp(a) on the expression of intercellular adhesion molecule (ICAM)-1, vascular cell adhesion molecule (VCAM)-1, and E-selectin in human umbilical vein endothelial cells by a cell ELISA. Lp(a) dramatically enhanced the levels of ICAM-1 in a dose-dependent manner. A discernible increase in ICAM-1 expression was observed at a physiological concentration of 0.26 mmol cholesterol/L Lp(a) after 48-hour incubation. A 1.8-fold increase in ICAM-1 expression was observed 48 hours after the addition of Lp(a) (1.04 mmol cholesterol/L). Northern blot analysis demonstrated that the amount of ICAM-1 mRNA was increased after treatment with Lp(a). In contrast to ICAM-1, the expression of VCAM-1 and E-selectin was not significantly affected by Lp(a). Lp(a-) [apolipoprotein(a)- removed Lp(a) by reduction with dithiothreitol] and LDL had no significant effect on the expression of ICAM-1. In contrast, recombinant apolipoprotein(a) protein alone significantly enhanced ICAM-1 expression. Lp(a) decreased the level of active transforming growth factor (TGF)-beta in the conditioned medium. Furthermore, recombinant TGF-beta significantly decreased the Lp(a)-induced ICAM-1 expression. These findings suggested that Lp(a) may enhance the ICAM-1 expression by decreasing active TGF-beta level. Lp(a) could contribute to the development of cardiovascular diseases by enhancing the expression of ICAM-1 in endothelial cells.

Contribution of a missense mutation (Trp64Arg) in beta3-adrenergic receptor gene to multiple risk factors in Japanese men with hyperuricemia.

Epidemiological data reveal that hyperuricemia is a risk factor of atherosclerosis. The risk is possibly caused by a link between hyperuricemia and insulin resistance-related metabolic syndrome. Recently it has been proposed that a missense mutation (Trp64Arg) in the beta3-adrenergic receptor (beta3-AR) gene may contribute to the accumulation of multiple risk factors related to insulin resistance. The present study was undertaken to further clarify an association between the Trp64Arg mutation and the metabolic syndrome in 47 Japanese men with hyperuricemia, who are substantially at high risk of atherosclerosis. One patient (2%) had the homozygous mutation, 12 (26%) were heterozygous for the mutation, and 31 (72%) had no mutation found by the PCR-RFLP analysis. The Trp64Arg mutation was not related to past maximal body mass index (BMI), BMI and waist/hip ratio. The subjects with the heterozygous mutation showed a slightly higher incidence of impaired glucose tolerance and diabetes mellitus in the 75 g oral glucose challenge (67%), as compared with those without the mutation (39%). Serum insulin response at 60 min and the sum of serum insulin in the glucose challenge were greater in the former subjects than those in the latter subjects (P=0.041 and 0.076, respectively). An increase in serum lipoprotein(a) was also observed in the subjects with the heterozygous mutation, but the Trp64Arg mutation was not associated with other dyslipidemia, blood pressure or ischemic changes on the electrocardiogram. These results indicate that the heterozygous mutation of Trp64Arg in the beta3-AR gene partly contributes to the accumulation of multiple risk factors in male subjects with hyperuricemia. A larger prospective study is necessary to elucidate a possible role of the Trp64Arg mutation in atherosclerotic diseases in future.

Effects of hormone-replacement therapy on hemostatic factors, lipid factors, and endothelial function in women undergoing surgical menopause: Implications for prevention of atherosclerosis

Women with premature menopause are at high risk for vascular compications associated with thrombogenesis and atherogenesis. The use of hormone-replacement therapy (HRT), however, may protect against these complications. Hemostatic abnormalities and endothelial function are closely related to the processes of thrombogenesis and atherogenesis. The purpose of the study was to evaluate the effects of premature menopause on markers of hemostasis, platelet function, and endothelial function and the effects of starting HRT. This is a prospective longitudinal study of premenopausal women undergoing surgical menopause in whom estrogen HRT is started. We measured sequential changes in plasma levels of the hemostatic factors (fibrinogen, fibrin d -dimer, and plasminogen activiator inhibitor [PAI]), markers of platelet function (soluble leukocyte adhesion molecule P-selectin) and endothelial function (von Willebrand factor [vWf], soluble thrombomodulin [sTM], and tissue plasminogen activator [TPA]), and serum lipid levels, including lipoprotein A. Twenty-seven premenopausal women (mean age 43.6 ± 6.5 years) undergoing hysterectomy and bilateral salpingo-oophrectomy were studied. In the postsurgical menopausal state (visit 2), there was a significant elevation in sTM levels (paired Wilcoxon test, p = 0.008). There was also a trend toward higher median soluble P-selectin, PAI, and mean TPA levels and lower vWf levels. After 6 weeks of HRT (visit 3), there was a significant reduction in mean vWf (paired Wilcoxon test, p = 0.0026), sTM ( p = 0.039), and TPA levels ( p = 0.02) compared with premenopausal levels. There were no significant changes in plasma fibrinogen, fibrin d -dimer, and PAI levels at visit 2 or visit 3 compared with premenopausal levels. There was a significant increase in serum lipoprotein A (paired Wilcoxon test, p = 0.008), cholesterol, and triglyceride levels after surgical menopause (paired t test, p < 0.01). Lipoprotein A and cholesterol levels after HRT (visit 3) were not significantly different from prehysterectomy levels, although triglyceride levels were increased further. HRT results in a significant reduction in vWf, sTM, and TPA levels, suggesting beneficial effects on endothelial function and atherogenesis. Although there was a significant increase in serum lipoprotein A and cholesterol levels after surgical menopause, lipoprotein A and cholesterol levels after HRT were not significantly different from presurgery levels. These observations are consistent with the beneficial effects of HRT in cardiovascular hemodynamics and cardiovascular disease. (Am Heart J 1997;134:764-71.)

抗酸化物質と動脈硬化

Atherosclerosis is principal contributor to the pathogenesis of myocardial and cerebral infarction, gangrene and loss of function in the extremities. The lesion result from an excessive inflammatoryfibrous proliferative response to various forms of insult to the endothelium and smooth muscle cell has been known as “response to injury hypothesis of atherosclerosis”. In recent years a large number of types of toxic injury and diseases has been linked with free radical-mediated disturbances. In many cases, implication has been that the free radical disturbance is causative in relation to the ensuing cell or tissue damage. LDL can be oxidatively modified via a free-radical mediated process. Oxidixzed LDL (ox-LDL) is a key component in endothelial injury. Once ox-LDL is formed, ox-LDL may directly injure the endothelium and play and initial role in the increased adherence and migration of monocytes and T-lymphocytes into the subendothelial space. The earliest recognizable lesion of atherosclerosis is the so-called fatty streak an aggregation of lipid-rich macrophages and T-lymphocytes within the innermost layer of the artery wall, the intima. As one of the cause of the endothelial injury, has been linked with free radical mediated alteration of low density lipoprotein (LDL), i. e., peroxidized LDL. Ox-LDL is a key compornent in endothelial injury which increased adherence of monocyte/macrophage and T-lymphocytes. The macrophages scavenge the ox-LDL and become large foam cells which accumulate in fatty streak. Lack of antioxidants participate ox-LDL formation and endothelial dysfunction. Ascorbic acid is most strong antioxidant in the tissue. The principle pathway of ascorbic acid oxidation and turnover is believed to involve the removal of two electron in succession, yielding firstly the ascorbate free radical (AFR) and then dehydroascorbate. AFR may be reduced by a micorosomal NADH dependent enzyme, monodehydro-L-ascorbate oxidase to ascorbate. Dehydroascorbate also reduced to ascorbate as shown in Fig. 1. Thus, ascorbic acid acts as redox or antioxidant as a biological role in hydrophobic state. We have reported ascorbic acid deficiency, scurvy induced not only endothelium injury of the capillary but also of the aorta in guinea pig as shown in Fig. 2. Scurvy also induced an increase in serum lipoproteins in guinea pig due to suppressed lipoprotein lipase activity and reduced cofactor for 7α-hydroxylase which is rate limiting enzyme in the process of cholesterol to bile acid metabolism. Marginal vitamin C deficiency for 8 weeks induced fatty streak without supplemental cholesterol feeding in guinea pig. Recently, scurvy prone osteo-dystrophic rat (ODS-rat) with lack of L-gulonolactone-α-oxidase was separated (Fig. 3). Kawai et al, reported that mutant cDNA of the rat has a single base mutation from guanosine (G) to adenine (A) at nucleotide 182, which mutation alters the 61st amino acid residue from cysteine to tyrosine. In the serum of the ODS-rat, we could not find apparent changes of serum lipids but found significant increase in oxidized lipid estimated as MDA (malon dialdehyde) and LPO (lipo-peroxide) as shown in Fig. 4. By electone microscopic observation of the ODS-rat aorta, we found several cells which might be macrophage or lymphocyte with vacuolar structure in the cytoplasma in subendothelial space (Fig. 5). The importance of ox-LDL in atherosclerosis was established through the use of the antioxidant, probucol, in studies of a genetic hyperlipidaemic rabbit as model of atherosclerosis. As a rosis. Numerous antioxidants have listed in Table 1. Vitamin C and E act synergistically, vitamin E act as the primary antioxidant and the resulting vitamin E radical then reacting with vatamin C to regenerate vitamin E. Still a question remains whether such an interaction between vitamin C and vatamin E radical can take place in biological systems. Niki revealed that vitamin C located in the aqueous region c

Do Gonadotropins Influence Serum Lipoprotein(a) Concentrations? Observations on Children, Adolescents and Adults

Data from 7045 subjects were examined. The main groups consisted of the following in- and outpatients: 1414 neonates, 2554 children and adolescents (1336 males, 1218 females), 1209 women directly postpartum, 786 non-pregnant women and 1090 men aged between 18 and 100 years of age. Unless otherwise stated, persons were under medical observation or therapy. The results were obtained over a three-year period using an in-house immunoluminometric assay specific for apolipoprotein(a) using two polyclonal antibodies and single lot of reagents to allow for comparability of results. Girls aged between 10 and 12 years of age had significantly higher serum lipoprotein(a) (median 124 mg/l) levels than boys (median 88 mg/l) of the same age (p < 0.05-Mann-Whitney U-test). Post-pubertal lipoprotein(a) concentrations were not significantly different from pre-pubertal levels. Between the ages of 0-9 and 13-17 years there were no statistically significant sex-linked differences in serum lipoprotein(a). In adults, lipoprotein(a) serum levels were significantly higher in women (median 163 mg/l) aged between 50 and 59 years, when compared with men (median 128 mg/l) of the same age group (p = 0.05-Kruskal-Wallis one way ANOVA followed by the Nemenyi test). There was no significant difference in serum lipoprotein(a) concentrations between healthy women (median 91 mg/l), women direct postpartum (median 116 mg/l) and in-patient women (median 117 mg/l) aged between 18 and 41 years of age (p = 0.11-0.96). There was no correlation between maternal lipoprotein(a) and birth weight in mature newborns (r = -0.028-0.085). The results may indicate a direct influence of gonadotropins at puberty and during the menopause which cause an increase in serum lipoprotein(a) concentrations.

(Apo)lipoprotein(a) concentrations at birth and in the first days and months of life--studies on the distribution of serum levels and the predictive value of measurements made at this time.

This study was carried out on 625 newborns delivered between July 1993 and December 1994 and 221 children visiting the clinic in the first year of life using an immunoluminometric assay specific for apolipoprotein(a), but calibrated with lipoprotein(a), hence the use of the term (apo)lipoprotein(a) for neonatal values. (Apo)lipoprotein(a) concentrations were measured in 278 neonates over the first 12 days of life (median observation time 6 days). A further 64 children were followed up over a period of 1-10 months (median observation time 5 months). The median (apo)lipoprotein(a) concentration at birth was 14.7 mg/l (males 14.6, females 14.7 mg/l). The range of concentrations measured was between 1 and 433 mg/l. The correlation coefficient between maternal and neonatal lipoprotein(a) at birth was 0.509 for 483 data pairs. The behaviour of serum concentrations of (apo)lipoprotein(a) during the first days of life varied greatly and was independent of the birth level. Eighty-four babies showed a decrease, 107 an increase and 87 no change in (apo)lipoprotein(a) levels; over the first months of life was more unified with 50 children showing an increase in serum lipoprotein(a), a decrease in 4 cases and no change in 10 cases. In these 64 children the median increase in serum (apo)lipoprotein(a) was from 15.8 mg/l at birth (range 1 to 364 mg/l) to 38.5 mg/l at 6 months. The median lipoprotein(a) concentrations in the children under 1 year (median age 6 months) was 37.0 mg/l (males 37.1, females 37.0 mg/l).(ABSTRACT TRUNCATED AT 250 WORDS)

Pathogenesis of postprandial hyperlipemia in rats fed ethanol-containing diets.

To study the mechanism of the increase in serum lipoproteins which occurs in rats fed alcohol chronically, and especially to assess the role of the intestine, the effects of acute and chronic ethanol administration on lymph and plasma lipids were compared in rats with and without intestinal lymph fistulae. In rats not previously given alcohol, the administration of one dose of a diet containing ethanol (3 g/kg) produced a significant increase in lymph flow, lipid output, and incorporation of dietary fat into lymph lipids when compared with the effects of a control diet containing isocaloric carbohydrate. However, no hyperlipemia developed after ethanol. By contrast, previous feeding of ethanol for several weeks modified the acute effects of ethanol on both lymph and serum lipids. Compared with control animals pair-fed with isocaloric carbohydrate-containing diets, rats which had been fed a diet with 36% of total calories as ethanol for 3-4 wk developed postprandial hyperlipemia when given a single dose of the ethanol-containing or even the ethanol-free diet. This was associated with an increased incorporation of labeled dietary fat and of intravenously injected [(3)H]lysine into plasma lipoproteins of d < 1.006. However, postprandial lymph flow and lipid output were not higher in rats fed alcohol chronically than in their pair-fed controls. Moreover, when rats with lymph fistulae were given intravenous (i.v.) infusions of lymph lipids (to substitute for the diverted intestinal lymph), the ethanol-fed animals still developed hyperlipemia. Incorporation of i.v. lysine into d < 1.006 plasma lipoproteins also remained significantly increased. Thus, under these conditions, alcoholic hyperlipemia does not result from changes in intestinal lymph lipids. Two main factors appear to be involved; the acute effects of ethanol on hepatic lipid metabolism and the development of an increased capacity for lipoprotein synthesis during chronic ethanol feeding. The latter most likely occurs in the liver and it is postulated that it is linked to the associated changes in the hepatic endoplasmic reticulum.

Serum lipoproteins of rats bearing transplanted Morris hepatoma 7777.

AbstractThe serum lipoprotein patterns of Buffalo‐strain rats bearing hepatoma 7777 were determined in the 2nd, 4th and 5th weeks after transplantation of the tumor. The result indicated the presence of a slow‐moving HDL component which was similar to that observed previously in Holtzman rats given 0.03% N‐2‐fluorenylacetamide. Five weeks after transplantation of the tumor, the serum lipoproteins were isolated ultracentrifugally and quantified by chemical analyses and by disc electrophoresis using a protein stain. These results have confirmed the increase in serum lipoproteins, especially the high density lipoprotein, HDL2, in these tumor‐bearing rats. The serum total lipid, cholesterol and phospholipid were considerably increased while the total serum proteins were only slightly elevated in rats with tumors as compared to control rats. A new α1‐globulin component was observed in the serum protein patterns in the tumor‐bearing rats.