Higher Apo Research Articles

Cholesterol absorption and synthesis related to low density lipoprotein metabolism during varying cholesterol intake in men with different apoE phenotypes.

The aim of the present study was, first, to investigate whether cholesterol (C) absorption, enhanced by cholesterol feeding, was related to synthesis of cholesterol, serum level of low density lipoprotein (LDL)-C, and receptor activity for LDL apolipoprotein (apo) B in healthy men. Secondly, we were interested in whether apolipoprotein E (apoE) phenotypes contributed to cholesterol and LDL apoB metabolism under these conditions. We studied 29 home-living men aged 55 +/- 1 (mean +/- SE) years on a low-fat, low cholesterol (208 +/- 13 mg/day) diet followed by a low-fat high cholesterol (878 +/- 38 mg/day) diet during 5 weeks. Cholesterol feeding increased total cholesterol, LDL-C, high density lipoprotein (HDL)-C, and LDL apoB levels from 10% to 13% (P less than 0.05) and bile acid production and cholesterol turnover by 16% (P less than 0.05), decreased the fractional catabolic rate (FCR) for LDL apoB by 10% (P less than 0.05) and cholesterol absorption efficiency by 8% (P less than 0.05), while cholesterol synthesis only tended to decrease. During the cholesterol feeding, LDL-C was positively related to apoB production rate and cholesterol absorption efficiency (P less than 0.05), and negatively related to bile acid and cholesterol synthesis (P less than 0.05) and FCR for LDL apoB, which, in turn, was negatively related to cholesterol absorption efficiency and positively to bile acid synthesis. ApoE phenotype was positively related to TC, LDL-C, and LDL apoB levels and negatively to FCR for LDL apoB. The increase of the LDL-C level by the high cholesterol intake was positively correlated with LDL-C on high cholesterol diet and apoE phenotypes, so that the increase was 7% in apoE2 (ns), 11% in apoE3 (P less than 0.05), and 18% in apoE4 (P less than 0.05); the increase of bile acid synthesis was significant only in subjects with apoE2. Moreover, the increase of LDL-C was positively related to the absolute amount of dietary cholesterol absorbed and negatively to FCR for LDL apoB. The findings suggest that the higher the LDL-C level, the higher is the absorption efficiency of cholesterol and production of LDL apoB, and the lower is the removal of LDL apoB and synthesis of both bile acids and cholesterol, and the more frequently the subjects had epsilon 4 allele. The nonresponsiveness to dietary cholesterol was dependent on low LDL-C level, apoE2 phenotype, and effective bile acid synthesis.(ABSTRACT TRUNCATED AT 400 WORDS)

Significant association between low-molecular-weight apolipoprotein(a) isoforms and intermittent claudication.

The role of lipoprotein(a) (Lp[a]) and apolipoprotein(a) (apo[a]) isoforms in symptomatic peripheral atherosclerosis was studied in 100 randomly selected middle-aged (45-69 years) men with intermittent claudication (IC) and 100 randomly selected healthy control (C) subjects. IC and C subjects were matched pairwise for sex, age, and smoking habits. Plasma Lp(a) concentrations were significantly higher in IC subjects, with a median value of 20.12 mg/dl, compared with 11.11 mg/dl in C subjects (p less than 0.0009). The elevated Lp(a) concentration was to a great extent due to a significant difference in the frequency distribution of apo(a) isoforms between IC and C subjects (p less than 0.029). Low-molecular-weight apo(a) isoforms were more prevalent in IC than C subjects. Also, IC subjects with apo(a) S2 and S3 phenotypes had higher Lp(a) concentrations than control subjects with the same phenotypes: S2:60.70 mg/dl (IC) and 48.69 mg/dl (C), p less than 0.038; and S3: 30.18 mg/dl (IC) and 12.01 mg/dl (C), p less than 0.042, so other still-unknown factors, genetic or nongenetic, may be important. Stepwise logistic regression analysis demonstrated that Lp(a) concentration contributed significantly (p less than 0.0002) to IC, independent of age, smoking, hypertension, diabetes mellitus, plasma total cholesterol, low density lipoprotein cholesterol, high density lipoprotein cholesterol, apo B, and plasma total triglycerides. Apo(a) isoforms grouped according to molecular weight were also independent of the above risk factors associated (p = 0.016) with the occurrence of IC because of their low-molecular-weight but were not independent of Lp(a) concentrations.(ABSTRACT TRUNCATED AT 250 WORDS)

Familial lipoprotein disorders in patients with premature coronary artery disease.

Genetic lipoprotein disorders have been associated with premature coronary artery disease (CAD). The prevalence of such disorders was determined in 102 kindreds (n = 603 subjects) in whom the proband had significant CAD documented by angiography before the age of 60 years. Fasting plasma cholesterol, triglyceride, low density lipoprotein (LDL) cholesterol, apolipoprotein (apo) B, and lipoprotein (a) [Lp(a)] values above the 90th percentile and high density lipoprotein (HDL) cholesterol and apo A-I below the 10th percentile of age- and sex-specific norms were defined as abnormal. An abnormality was noted in 73.5% of probands compared with 38.2% in age-matched controls (p less than 0.001), with a low HDL cholesterol level (hypoalphalipoproteinemia) being the most common abnormality (39.2% of cases). In these kindreds, 54% had a defined phenotypic familial lipoprotein or apolipoprotein disorder. The following frequencies were observed: Lp(a) excess, 18.6% (includes 12.7% with no other dyslipidemias); hypertriglyceridemia with hypoalphalipoproteinemia, 14.7%; combined hyperlipidemia, 13.7% (11.7% with and 2.0% without hypoalphalipoproteinemia); hyperapobetalipoproteinemia (elevated apo B only), 5%; hypoalphalipoproteinemia, 4%; hypercholesterolemia (elevated LDL only), 3%; hypertriglyceridemia, 1%; decreased apo A-I only, 1%. Overall, 54% of the probands had a familial dyslipidemia; unclassifiable lipid disorders (spouse also affected) were found in 3%. No identifiable familial dyslipidemia was noted in 43% of kindreds of those; nearly half (45%) had a sporadic lipid disorder. Parent-offspring and proband-spouse correlations for these biochemical variables revealed that lipoprotein and apolipoprotein levels are in part genetically determined, with Lp(a) showing the highest degree of parent-offspring correlation. Our data indicate that more than half of patients with premature CAD have a familial lipoprotein disorder, with Lp(a) excess, hypertriglyceridemia with hypoalphalipoproteinemia, and combined hyperlipidemia with hypoalphalipoproteinemia being the most common abnormalities.

Plasma Apolipoproteins A-I, A-II, B, C-II, C-III, and E Levels in Young Kuwaiti Male Survivors of Myocardial Infarction

Plasm levels of lipid, lipoprotein, and apolipoprotein (APO) A-I, A-II, C-II, C-III, and E were analyzed in 180 young survivors of myocardial infarction (MI) ages 28 to 45 years and in 200 sex-and age-matched normal healthy subjects to assess the importance of apolipoprotein concentrations in comparison with lipoproteins in MI patients. In comparison with control subjects, MI patients showed marked increases in the following parameters: total cholesterol (TC), low density lipoproteins (LDL) cholesterol, triglycerides (TG), very low density (VLDL) triglycerides, and cholesterol, and LDL-TG, apo B, apo C-III and apo E. There were no significant changes in levels of HDL3; cholesterol, apo A-II and apo C-II in these patients compared with their controls. Levels of high density lipoprotein (HDL), HDL2 cholesterol, and plasma apo A-I were markedly decreased in the young MI survivors' group demonstrated that the better discriminating lipoproteins and apolipoproteins in MI patients in descending order were HDL2 cholesterol, apo C-III, apo B, apo A-I, VLDL triglycerides and HDL cholesterol discriminated between patients and controls. Results indicate that measurement of apo C-III, B and A-I beside HDL2 cholesterol were shown to be of potential use in differentiating normal controls from patients with MI.

Metabolism of apolipoprotein B in members of a family with accelerated atherosclerosis: Influence of apolipoprotein E-3/E-2 pattern

Familial combined hyperlipidemia (FCHL) appears to be the most common, simply inherited hyperlipidemia strongly associated with coronary heart disease. In the family examined in this study, two of the siblings who met diagnostic criteria for FCHL had extensive clinical atherosclerosis before age 30, unusually premature for this form of hyperlipidemia. Lipoproteins and low-density lipoprotein (LDL) apolipoprotein (apo) B metabolism were characterized in these siblings in an attempt to gain insight into the cause of the rapid atherosclerosis in the two siblings so affected. LDL apo B production rates were very high in all three siblings (25 to 30 mg/kg/d), consistent with FCHL. β-Very-low-density, lipoprotein- β (β-VLDL) was present in the plasma of both siblings with accelerated atherosclerosis. The isoapolipoprotein E pattern in both of these siblings was E-3/E-2. In the third sibling, who was free of premature clinical atherosclerosis and lacked plasma β-VLDL, the pattern was E-3/E-3. Thus, the heterozygote apo E-3/E-2 pattern may be related to the accumulation of β-VLDL in persons with a very high apo B production rate. The abnormal accumulation of β-VLDL may be one of the possible explanations for the rapid, premature atherosclerosis in the two siblings with FCHL in this kindred. Both male members in this kindred also had low levels of high-density lipoproteins, and thus may have had an additional risk of developing atherosclerosis due to this lipoprotein abnormality as well.

Bimodality of plasma apolipoprotein B levels in familial combined hyperlipidemia

To investigate possible genetic influences on plasma apolipoprotein (apo) B levels in familial combined hyperlipidemia (FCHL), commingling analysis was performed on data from seven large kindreds, including 183 individuals. The overall frequency distribution of apo B was skewed and was compatible with the presence of two normally distributed subdistributions (mean values, 117 and 172 mg/dl). The analysis was repeated after stratification of individuals by low density lipoprotein (LDL) subclass phenotype. Among subjects with phenotype A (predominance of large, buoyant LDL), a single apo B distribution was found (mean, 115 mg/dl). Among subjects with phenotype B (predominance of small, dense LDL), the distribution was bimodal, with mean values, 116 and 167 mg/dl, similar to the unstratified data set. Thus the skewing of the overall apo B distribution in FCHL family members may be due to a distinct subset of individuals with phenotype B who are genetically susceptible to even higher elevations of apo B. The higher apo B/phenotype B subjects also showed significantly higher levels of triglyceride and LDL-cholesterol than the lower apo B/phenotype B subjects. The lower apo B/phenotype B subjects had higher triglyceride and lower LDL-cholesterol than the phenotype A subjects. The enhanced information regarding apo B and lipid levels in the three subgroups of individuals identified here may facilitate a better understanding of genetic susceptibility to coronary heart disease.

Apolipoprotein B-gene DNA polymorphisms (XbaI and EcoRI), serum lipids, and apolipoproteins in healthy Chinese.

The frequency of restriction fragment length polymorphisms (RFLPs) of the apolipoprotein B (apo B) gene, detected by XbaI and EcoRI, and their influence on serum lipids and apolipoproteins were studied in healthy Chinese of both sexes in Singapore. A total of 221 subjects (150 males, 71 females) were investigated for the XbaI and 159 subjects for the EcoRI polymorphisms, while serum lipids and apolipoprotein levels were available for 196 subjects. The frequency of the X2 allele was found to be significantly lower in the Chinese than that reported in Caucasians from the United Kingdom (0.09 vs. 0.51, P less than 0.001). The haplotype frequencies were also significantly different between the Chinese and Caucasians with a higher frequency of X1R1 in the former compared to the latter (0.85 vs. 0.34, P less than 0.0001). The distribution of RFLP genotypes at both of the restriction sites was at Hardy-Weinberg equilibrium in all groups. The influence of the apo B RFLPs on serum lipids and apolipoprotein levels (apo AI, AII, and B) was studied by both residual and multiple regression analyses considering age, sex, body mass index (BMI), and genotypes as independent variables in all possible combinations. No association was observed between the apo B genotypes and serum lipids or apolipoprotein levels except for high density lipoprotein cholesterol (HDLC), apo AI and AII, with the X2 being associated with significantly lower levels of HDLC as well as apo AI and AII, the effect being stronger in males. These data raise the possibility that the mechanism of reported association between apo B polymorphism and coronary artery disease may be through effects on HDLC.

Role of apolipoprotein E on cholesteryl ester-enriched low density lipoprotein particles in coronary artery atherosclerosis of hypercholesterolemic nonhuman primates.

Significant differences among individuals occur in the lipoprotein response to atherogenic diets in cynomolgus and African green monkeys. The range of concentrations of total plasma cholesterol (TPC) was 100-600 mg/dl and of apolipoprotein (apo) E (quantified by enzyme-linked immunosorbent assay) was 3-20 mg/dl in the animal groups of this study. The correlation between the concentrations of TPC and of apo E was r = 0.89 in these animals. To determine which lipoprotein classes contained the majority of apo E, agarose gel-filtration chromatography was used to subfractionate whole plasma. In hypercholesterolemic monkeys, the majority of the apo E and apo B-100 coeluted within the region of low density lipoprotein (LDL). In normocholesterolemic monkeys, the majority of apo E coeluted with apo A-I and high density lipoproteins. A strong positive correlation was seen between the concentrations of plasma apo E and LDL cholesterol (r = 0.9), but there was no significant correlation between high density lipoprotein apo E and either TPC or plasma apo E concentrations. A positive correlation of r = 0.8 was found between the LDL apo E to apo B-100 molar ratio and the average LDL particle size, suggesting an increase in the number of apo E molecules on the larger LDL particles. Within individual animals, LDL were heterogeneous and the LDL subfractions of lower density (1.02 less than d less than 1.03 g/ml) had the highest proportion of apo E, although apo E was present on LDL of all densities. A strong positive correlation between plasma apo E concentration and coronary artery atherosclerosis was identified, and in stepwise regression analysis, plasma apo B concentration and the apo E to apo B molar ratio of LDL together accounted for more than 90% of the variation in the atherosclerosis end point of coronary artery intimal area. These data strongly suggest that the enrichment of LDL with cholesteryl esters and apo E, which occurs in hypercholesterolemic primates, is an atherogenic feature of the plasma lipoproteins.

Apolipoproteins A-I and B and the B/A-I Ratio in the First Year of Life

To investigate early detection of young families with inherited dyslipidemia, we assessed changes in circulating apolipoprotein (apo) B and A-I levels and the apo B/A-I ratio during the 1st year of life and their relations to parental values. After measuring initial dried blood spot capillary blood levels in 919 babies when aged 4.25 +/- 0.98 d (mean +/- SD), we recalled at a mean age of 8.5 +/- 2.3 mo those with levels in one or more of the following categories: the top 5% of apo B values (group 1), the top 5% of apo B/A-I ratios (group 2), the bottom 5% of apo A-I values (group 3), and a group of 18 infants (group 4) who were not in any of the above three categories. We thus obtained serum lipid measurements in 51 infants and their parents. Two of the 13 group 1 infants had persistent hyperapo B at 8.5 mo; there was an inverse relationship between apo B and apo A-I levels in this group (p less than 0.001). Two of 11 babies in group 2 had lipid profiles consistent with familial hypercholesterolemia. However, none of the infants in group 3 had evidence at 8.5 mo of abnormal apo A-I or HDL levels, nor did their parents. For groups 1, 2, and 3, there was at 8.5 mo a regression of apo B and A-I toward mean levels for the "normal" 18 babies of group 4. In contrast, the high apo B/A-I ratios in group 2 remained high (p less than 0.01) and showed evidence of tracking.(ABSTRACT TRUNCATED AT 250 WORDS)

Contribution of the apo[a] phenotype to plasma Lp[a] concentrations shows considerable ethnic variation.

Apolipoprotein[a] polymorphism has been investigated by sodium dodecyl sulfate polyacrylamide (5.37%) gel electrophoresis and immunoblotting using a standardized sample load in four ethnic groups: German, Ghanaian, Chinese, and San (Kalahari Bushmen). A total of 10 different apparent molecular weight (Mr) polymorphs, designated 1 to 10 with increasing Mr, were detected in greater than 99% of all individuals tested (German, 99%; Ghanaian, 99%; Chinese, 100%; San 100%). A null allele is therefore at most an infrequent variant in all populations. Polymorphs 6-10 were common to all four populations, while polymorphs 1-5 appeared to be relatively rare variants not universally detected in each group in the present study. The Chinese had the highest proportion of double-band phenotypes and the observed frequencies were not significantly different from those expected according to simple Mendelian inheritance, whereas the observed apo[a] phenotype distributions of the other three groups did not concur with those expected for Hardy Weinberg equilibrium. The German and Ghanaian groups displayed similar distributions of apo[a] phenotypes while the Chinese and San had significantly higher frequencies of polymorphs 9 and 10. Mean plasma Lp[a] concentrations in Ghanaians (36.2 +/- 31.5 mg/dl) were almost 2-fold greater than in Germans (18.7 +/- 23.1 mg/dl) and ca 1.65-fold greater than in either Chinese (22.9 +/- 18.3 mg/dl) or San (21.1 +/- 19.3 mg/dl). A strong inverse correlation was observed between apo[a] Mr and plasma Lp[a] concentration in Germans but this was much less pronounced in Ghanaians. While the mean plasma Lp[a] levels associated with polymorphs 1-6 were similar in both Germans (43.4 +/- 30.0 mg/dl) and Ghanaians (49.2 +/- 37.6 mg/dl), those Ghanaians with any combination of the polymorphs 9 and 10 had an almost 3-fold greater mean plasma Lp[a] level (20.6 +/- 11.3 mg/dl) than their German counterparts (7.8 +/- 5.7 mg/dl). It is therefore apparent that: 1) differences in apo[a] allele frequencies are not primarily responsible for differences in Lp[a] levels between populations; and 2) the greatest ethnic variation is observed in plasma Lp[a] concentrations associated with the high molecular weight apo[a] polymorphs.

Plasma apolipoprotein A-I, A-II, B, E and C-III containing particles in men with premature coronary artery disease

Lipoprotein (Lp) cholesterol and apolipoproteins (apo) A-I and B levels have been shown to be better markers for the presence of coronary artery disease than total cholesterol. In this study, we determined the plasma levels of lipoprotein particles containing apo A-I only (LpA-1), apo A-I and A-IL (LpA-I:A-1I), apo B and C-III (LpB:C-III) and apo B and E (LpB:E) in 145 patients with coronary artery disease (mean age ± SD, 51 ± 7 years) and 135 healthy control men (mean age 49 ± 11 years). Patients with CAD had lower high density lipoprotein (HDL) cholesterol and apo A-I levels and higher triglycerides and apo B levels than controls. In patients with CAD, LpA-I (0.341 ± 0.093 vs. 0.461 ± 148 g/1) and LpA-1:A-II (0.694 ± 0.171 vs. 0.899 ± 0.148 g/1) were lower, whereas LpB:E (0.372 ± 0.204 vs. 0.235 ± 0.184 g/1) were higher than in controls (cases vs. controls, all P < 0.005). No significant differences were observed for LpB:C-III (0.098 ± 0.057 vs. 0.107 ± 0.061 g/1, p = 0.235) particles. Discriminant analysis indicates that LpA-II:A-I, LpE:B, LpA-I, and triglycerides best differentiate between cases and controls. Plasma apo C-III (0.027 ± 0.008 vs. 0.036 ± 0.020 g/1) and E (0.040 ± 0.015 vs. 0. 055 ± 0.029 g/1) were lower in the CAD group ( P < 0.001). The finding that apo C-III and E levels are lower in the CAD patients relate to the fact that in our patients, HDL particles are the main carriers of apo E and C-III and that in addition to HDL-cholesterol, the protein component of HDL particles are reduced in CAD. We conclude that apo B, LpB:E but not LpB:C-III containing particles are increased in patients with CAD and that apo A-I containing particles, with or without apo A-II are reduced in patients with CAD. In addition, HDL-cholesterol and associated apolipoproteins (A-I, A-11, C-III and E) are reduced in CAD.

Relationships of serum plant sterols (phytosterols) and cholesterol in 595 hypercholesterolemic subjects, and familial aggregation of phytosterols, cholesterol, and premature coronary heart disease in hyperphytosterolemic probands and their first-degree relatives

To assess relationships of serum phytosterols (plant sterols [P]) to serum cholesterol (C), P were measured by gas-liquid chromatography (GLC) in 595 hypercholesterolemics (top C quintile in screening of 3,472 self-referred subjects). A second specific aim was to determine whether high serum P would track over time and whether they would predict familial aggregation of high C, high low-density lipoprotein cholesterol (LDLC), high apolipoprotein (apo) B, and increased premature coronary heart disease (CHD) in hyperphytosterolemic probands and their first-degree relatives. Mean ± (SD) C was 260 ± 56 mg/dL, campesterol (CAMP) was 2.10 ± 1.6 μg/mL, stigmasterol (STIG) 1.71 ± 1.67, sitosterol (SIT) 2.98 ± 1.61, and total P 6.79 ± 3.66 μg/mL. Serum C correlated with CAMP ( r = .15, P ≤ .001), STIG ( r = .10, P ≤ .02), SIT ( r = .34, P ≤ .0001), and total P ( r = .29, P ≤ .0001). High serum CAMP and STIG were associated with a personal or family history of CHD in subjects less than or equal to age 55 years (premature CHD). In 21 hyperphytosterolemic probands who initially had at least one P at or above the 95th percentile and a second P at or above the 75th percentile, P were remeasured 2 years later. Initial and 2-year follow-up CAMP, STIG, and SIT did not differ ( P > .7). Initial and follow-up CAMP were correlated ( r = .47, P = .03). There was a history of premature CHD in 42% of the hyperphytosterolemic probands' kindreds, more than twice that (19%) in the full cohort ( χ 2 = 6.2, P = .013). Of 34 first-degree relatives of the 21 high-P probands, 11 (32%) had top decile C, 3.2 times expected, χ 2 = 5.8, P = .016, and 79% had top decile apo B, 7.9 times expected, χ 2 = 33.4, P < .00001. Probands' CAMP, SIT, and P were significantly positively correlated with their 34 first-degree relatives' C, LDLC, and triglyceride levels. Probands' CAMP and P correlated with relatives' apo B. In the 34 first-degree relatives, P were correlated with C, high-density lipoprotein cholesterol (HDLC), and apo A1; CAMP and SIT correlated with HDLC, and with apo A1. High P tracks, correlates closely with and predicts high C, high LDLC, and high apo B in families, and appears to be associated with increased premature CHD, independent of cholesterol. Increased absorption of all dietary sterols with resultant high P and high C may be a heritable, atherogenic trait separate from the rare, recessive familial sitosterolemia.

Nutrient intake comparisons between Framingham and rural and Urban Puriscal, Costa Rica. Associations with lipoproteins, apolipoproteins, and low density lipoprotein particle size.

To assess cross-cultural relations between dietary intake and plasma lipoproteins, we randomly selected 222 men and 243 women from the urban and rural areas of Puriscal, Costa Rica; related their dietary composition (assessed by a food-frequency questionnaire), fitness level, and body fat to plasma lipids, apolipoproteins, and low density lipoprotein (LDL) particle size; and compared these data with those from a subsample of 280 adults from the Framingham Offspring Study. Total cholesterol and LDL cholesterol levels were significantly (p less than 0.0001) higher in Framingham (207 and 137 mg/dl, respectively) than in Puriscal (184 and 114 mg/dl, respectively) residents. Elevated triglyceride and apolipoprotein (apo) B levels (25% and 16% higher), low HDL cholesterol and apo A-I levels (12% and 29% lower), and smaller LDL particles (17%) were more frequent in Puriscal than in Framingham residents. Urban Puriscal residents had a significantly lower fitness level; increased body fat, total cholesterol, and triglyceride levels; decreased HDL cholesterol in men; and higher apo B levels in women compared with rural Puriscal residents. Body fat, animal fat, and saturated fat intakes were significantly correlated with total cholesterol, LDL cholesterol, and apo B levels in both men and women in Puriscal. Intakes of protein and animal fat were higher among urban (10.7% and 14.1%, respectively) compared with rural (8.9% and 9.9%, respectively) Puriscal residents and in Framingham (16.0% and 20.8%, respectively) compared with Puriscal residents. No significant differences were found in dietary cholesterol. Saturated fat (largely from palm oil in Puriscal) intakes were significantly different among the three groups: rural Puriscal, 10.7% of calories; urban Puriscal, 11.6%; and Framingham residents, 12.9%. These data indicate that the more atherogenic plasma lipid profile among urban compared with Puriscal residents was largely explained by increased adiposity, decreased fitness level, and higher saturated fatty acid intake. Puriscal residents consumed less animal fat and more carbohydrate than did Framingham residents, and these differences were associated with a 21% lower LDL cholesterol level, a 12% lower HDL cholesterol level, a 29% lower apo A-I level, a 25% higher triglyceride level, a 16% higher apo B level, and a 17% smaller LDL particle size. Some of these cross-cultural differences may be due to differences in ethnic background and physical activity as well.

Relationship between apo[a] isoforms and Lp[a] density in subjects with different apo[a] phenotype: a study before and after a fatty meal

Plasma Lp[a] levels and apo[a] isoform distribution among lipoproteins isolated by density gradient ultracentrifugation were studied in subjects with one-band or two-band apo[a] phenotypes as assessed by gradient gel electrophoresis before and after an oral fat load. There were no significant differences in the ultracentrifugal profile between fasting plasma and postprandial plasma that was freed of triglyceride-rich particles (TRP). One-band phenotypes exhibited a single symmetrical peak in the density gradient, whereas two-band phenotypes exhibited a multi-modal distribution. Low molecular weight apo[a] isoforms were preferentially associated with low density Lp[a] whereas high molecular weight apo[a] isoforms were found with high density Lp[a] particles. Feeding a high fat meal caused no significant increase in the total plasma level of Lp[a]. However, the isolated TRP contained the apoB-100-apo[a] complex in a quantity that represented only about 1% of its total amount in the fasting plasma. In all cases the apo[a] isoforms present in TRP were also present in the fasting plasma; however, in the two-band apo[a] phenotypes the ratio of the slow over the fast migrating band was in all cases about eightfold higher in TRP than in the fasting plasma. These observations indicate that postprandially a small percentage of apoB-100-apo[a] associates with TRP and suggest that this complex may derive from de novo synthesis rather than from a pre-existing Lp[a] plasma pool. The liver would be the source of the complex due to the presence in the latter of apoB-100.

Lipoproteins in Children Treated with Continuous Peritoneal Dialysis

Total lipids, lipoprotein-lipids, and apolipoproteins were studied in plasma of 20 patients, aged 13.9 +/- 3.4 y (mean +/- SD; range 7.4 to 19 y), who were treated with continuous peritoneal dialysis for a period of 2.1 +/- 1.2 (range 0.5 to 4.9) y. Measurements included total plasma cholesterol and triglycerides, triglycerides in the very low density fraction, and cholesterol in the very low density, low density, and high density fractions, as well as apo A-I and apo B. The results were compared with values in 17 healthy control subjects, aged 13.0 +/- 5.1 (range 5.1 to 19) y. The patients had significantly elevated levels of total plasma triglycerides, triglycerides in the very low density fraction, total plasma cholesterol, cholesterol in the very low density fraction, and cholesterol in the low density fraction, whereas levels of cholesterol in the high density fraction were normal. Plasma apo B levels were elevated, but apo A-I levels were not different from controls. In addition, the nutritional status of the patients was assessed and apo A-I and apo B concentrations were measured in the dialysate of 10 patients. The losses of apo A-I and apo B in dialysate averaged 13.4 +/- 7.4 and 2.1 +/- 3.1 mg/kg/d, respectively. Lipoprotein profiles were not correlated with nutritional status. We conclude that pediatric patients treated with continuous peritoneal dialysis have atherogenic lipoprotein profiles, cholesterol ratios, and apolipoprotein ratios, but normal cholesterol in the high density fraction and apo A-I levels despite considerable apo A-I losses in the dialysate.

A characterization of copper/zinc superoxide dismutase mutants at position 124 Zinc‐deficient proteins

Substitution of the completely conserved aspartic acid residue at position 124 of Cu,Zn superoxide dismutase with asparagine and glycine has been performed through site-directed mutagenesis on the human enzyme. Asp124 is H-bonded to the NH of two histidines, one of which is bound to copper and the other to zinc. The mutant proteins, as expressed in Escherichia coli, result in an essential zinc-free enzyme which is similar to that obtained from the wild-type derivative through chemical manipulation. Only by extensive dialysis against 0.5 M ZnCl2 or CoCl2 at pH 5.4 was it possible to reconstitute approximately 50% of the molecules in the Cu2Zn2 or Cu2Co2 form. The new derivatives have been characterized through EPR, CD and nuclear magnetic relaxation dispersion techniques. The Cu2Cox derivatives (x approximately 1) were used to monitor, through electronic and 1H-NMR spectroscopies, the metal sites which are found to be similar to those of the wild type. In addition, a double substitution with asparagine has been made, replacing the invariant aspartate at position 124 and the highly conserved aspartate at position 125. The behavior is similar to that of the other mutants in most respects. The Cu2E2 (E = empty) derivatives of the mutants are stable, even in the pH range 8-10, whereas in the case of the Cu2E2 derivative of the wild type, copper migration occurs at high pH, producing both Cu2Cu2 and apo derivatives. The activity measurements indicate that the various Cu2E2 derivatives have the same activity at low pH and similar to that of the holoenzyme. A full profile up to pH 10.5 was obtained for the mutants.

Developmental Changes in Plasma Apolipoproteins B and A-I in Fetal Bovines

Plasma lipid, apolipoprotein (apo) B and apo A-I concentrations were measured in fetal calves in the age range of 4-9 months. The results were compared with those obtained from preruminant calves and cows. The studied lipids and apolipoproteins underwent quantitative underwent quantitative changes during development. Fetal calves, as compared to preruminant calves and cows, had a particularly low apo A-I concentration and a high apo B/apo A-I ratio. Unlike adult animals which have two forms of apo B, fetal calves had only high molecular weight apo B (apo Bh). During fetal development triglyceride, cholesterol and apo B concentrations decreased, but apo A-I concentrations remained constant.

老年早期における運動耐容能と心血管系危険因子

Evidence suggests that physical activity is related to lower coronary risk factors in middle-aged subjects, but to date data are lacking for older persons. A total of 32 healthy male subjects in their seventh decade (64 +/- 3 years) were divided into 2 groups based on maximal exercise tests (Bruce protocol). Group I consisted of 14 individuals who showed "excellent" work capacity (exercise duration of greater than or equal to 10 min, 11 +/- 1 min), and Group II 18 individuals with "fair" work capacity (7.5 +/- 1 min). None of them showed ECG evidence of ischemia in these tests. As compared with Group II, Group I showed lower casual and 24 hour ambulatory blood pressure (136 +/- 21 vs 114 +/- 11 mmHg for the average daily systolic pressure respectively), higher apo A-I levels (116 +/- 36 vs 139 +/- 20 mg/dl) and lower apo B/A-I ratios. There was no significant difference in triglycerides, total and HDL cholesterol or apo-B levels between these two groups. Body mass index and smoking habits were similar in Groups I and II. These results suggest that even in older persons, excellent physical fitness is related to lower cardiovascular risk factors.

A phenocopy of type III dysbetalipoproteinemia occurring in a candidate family for a putative apo E receptor defect.

On theoretical grounds, an apo E receptor defect should be manifested by the accumulation of lipoprotein remnants that are normally cleared by this receptor and cannot be processed by the normal apo B, E receptor (LDL-receptor). Furthermore, the defect should not be selective for a specific apo E phenotype since none of the isoforms would be cleared preferentially. Our search for such an occurrence led us to the discovery, in five members of a family of ten, of a unique dyslipoproteinemia mimicking type III. As in type III, plasma levels of cholesterol, triglycerides, VLDL-cholesterol, VLDL-triglycerides and apo E, as well as the VLDL-C/TG ratio, were high. LDL-cholesterol and HDL-cholesterol tended to be low. The clearance of plasma triglycerides after a fat load was impaired. Tubero-eruptive xanthomas, arcus corneae and manifestations of atherosclerosis were present in some individuals. In contrast to type III, the dyslipoproteinemia occurred in subjects bearing three different apo E phenotypes: E4/2, E4/3 and E3/2. VLDL-apo B levels were markedly increased, the VLDL-C/VLDL-B ratio was low and a double pre-beta band was present on lipoprotein electrophoresis. In spite of high apo E and borderline high apo CIII plasma levels, levels of the lipoprotein particles LpCIII:B and LpE:B, which characterize type III, were not raised. Rapid weight loss or treatment with a fibrate was observed to normalize the lipoprotein profile. It is surmised that the apo E-rich lipoprotein particles accumulating in this type III phenocopy with "hyperapoprebetalipoproteinemia" could be those that are normally cleared by an apo E receptor.

Treatment with hydroxymethylglutaryl-coenzyme A reductase inhibitors in hypercholesterolemia induces changes in the components of the extrinsic coagulation system.

The present study was performed to determine the influence of pharmaceutical intervention on parameters of blood coagulation and fibrinolysis in hypercholesterolemic patients. Eighteen otherwise-healthy individuals with heterozygous familial hypercholesterolemia were treated with a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor (simvastatin, 40 mg daily) for 12-14 weeks followed by additional treatment with omega-3 fatty acids (equivalent to 4 g eicosapentaenoic acid/docosahexaenoic acid daily) for 6 more weeks. With simvastatin treatment, the mean decreases in total cholesterol, low density lipoprotein (LDL) cholesterol, and apolipoprotein B (apo B) were 39%, 46%, and 36%, respectively. Only minor changes in high density lipoprotein (HDL) cholesterol and apo A-1 were recorded. omega-3 fatty acids had minor additional effects. The most prominent effects on the blood coagulation system were the changes in extrinsic pathway inhibitor (EPI), which is the inhibitor of the factor VIIa-tissue thromboplastin complex. EPI activity decreased from a median of 153% to 111% (p less than 0.001) with simvastatin treatment and to 112% (p less than 0.001) on the combined regimen. EPI activity was significantly correlated with LDL cholesterol (r = 0.78), total cholesterol (r = 0.77), apo B (r = 0.65), and apo A-1 (r = 0.45). Multiple stepwise regression analysis showed that LDL cholesterol was the most important predictor of EPI activity, which suggests that a majority of EPI activity in plasma is associated with LDL. Moreover, the alteration in EPI activity was correlated closely with the corresponding alteration in LDL, which suggests a direct relation between a coagulation-inhibitor activity and a pharmaceutical lipid-related response.(ABSTRACT TRUNCATED AT 250 WORDS)