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Biomedical subjects

J S Cohn

Publications and source records attributed to J S Cohn.

At least 37 records · Page 2Linked to original sources
PubMed1998

Plasma remnant-like particle lipid and apolipoprotein levels in normolipidemic and hyperlipidemic subjects.

Remnant-like particle (RLP) lipid and apolipoprotein (apo) levels were determined in the plasma of normolipidemic and hyperlipidemic subjects, in order to investigate the relationship between RLP levels and the concentration of other plasma lipoprotein parameters. Plasma RLP fractions were isolated with the use of an immunoaffinity gel (RLP-Cholesterol Jimro II, Japan Immunoresearch Lab.), containing specific anti-apoB-100 and anti-apoA-I antibodies. Four groups of human subjects were selected, who had either matching or significantly different levels of plasma triglyceride (TG) and low-density lipoprotein cholesterol (LDL-C): (1) normolipidemic control (NC) subjects (n = 10), (2) patients with elevated levels of LDL-C (type IIa, LDL-C (mean +/- S.E.), 4.65 +/- 0.09 mmol/l, n = 10), (3) hypertriglyceridemic (HTG) patients with elevated LDL-C (type IIb, TG: 3.86 +/- 0.36; LDL-C: 4.67 +/- 0.21 mmol/l, n = 10), and (4) HTG patients with normal LDL-C (type IV, TG: 3.71 +/- 0.39 mmol/l, n = 10). NC subjects (RLP-C: 0.22 +/- 0.01; RLP-TG: 0.24 +/- 0.03 mmol/l) had RLP apoB, apoC-III and apoE levels of 3.2 +/- 0.3, 1.8 +/- 0.3, and 1.4 +/- 0.1 mg/dl, representing 3.2 +/- 0.4, 14.5 +/- 1.4 and 32.1 +/- 2.1% of total plasma levels, respectively. RLP lipid and apolipoprotein concentrations were significantly higher in HTG groups (type IIb and IV) compared to NTG groups (NC and type IIa) (e.g. RLP-C: 0.50 +/- 0.07 and 0.58 +/- 0.11 vs. 0.22 +/- 0.01 and 0.21 +/- 0.01 mmol/l, respectively (P < 0.01); RLP apoB: 8.4 +/- 1.6 and 8.2 +/- 0.9 vs. 3.2 +/- 0.3 and 3.4 +/- 0.2 mg/dl, respectively (P < 0.01)). No significant difference in RLP levels was observed between groups having different LDL levels, and thus no correlation existed between RLP-C and LDL-C levels (r = 0.24, n.s.). RLP-C and RLP apoB levels were, however, correlated with VLDL-C and VLDL apoB (r = 0.86, P < 0.001 and r = 0.70, P < 0.001, respectively). These results demonstrate that elevated levels of both RLP lipids and apolipoproteins are characteristic of patients with increased levels of plasma triglyceride, and not patients with increased levels of LDL.

Adult↗
PubMed1998

Familial HDL deficiency characterized by hypercatabolism of mature apoA-I but not proapoA-I.

We have previously described patients with familial high density lipoprotein (HDL) deficiency (FHD) having a marked reduction in the plasma concentration of HDL cholesterol and apolipoprotein (apo) A-I but lacking clinical manifestations of Tangier disease or evidence of other known causes of HDL deficiency. To determine whether FHD in these individuals was associated with impaired HDL production or increased HDL catabolism, we investigated the kinetics of plasma apoA-I and apoA-II in two related FHD patients (plasma apoA-I, 17 and 37 mg/dL) and four control subjects (apoA-I, 126+/-18 mg/dL, mean+/-SD) by using a primed constant infusion of deuterated leucine. Kinetic analysis of plasma apolipoprotein enrichment curves demonstrated that mature plasma apoA-I production rates (PRs) were similar in patients and control subjects (7.9 and 9.1 versus 10.5+/-1.7 mg x kg[-1] x d[-1]). Residence times (RTs) of mature apoA-I were, however, significantly less in FHD patients (0.79 and 1.66 days) compared with controls (5.32+/-1.05 days). Essentially normal levels of plasma proapoA-I (the precursor protein of apoA-I) in FHD patients were associated with normal plasma proapoA-I PRs (7.8 and 10.4 versus 10.9+/-2.6 mg x kg[-1] x d[-1]) and proapoA-I RTs (0.18 and 0.15 versus 0.16+/-0.03 day). The RTs of apoA-II were, however, less in patients (3.17 and 2.92 days) than control subjects (7.24+/-0.71 days), whereas the PRs of apoA-II were similar (1.8 and 1.9 versus 1.7+/-0.2 mg x kg[-1] x d[-1]). Increased plasma catabolism of apoA-II in FHD patients was associated with the presence in plasma of abnormal apoA-II-HDL (without apoA-I). These results demonstrate that FHD in our patients is characterized, like Tangier disease, by hypercatabolism of mature apoA-I and apoA-II, but unlike Tangier disease, by essentially normal plasma catabolism and concentration of proapoA-I.

Apolipoprotein A-I↗
PubMed1998

In vitro factors affecting the concentration of gamma-LpE (gamma-LpE) in human plasma.

Gamma-LpE (gamma-LpE), a sphingomyelin-rich lipoprotein that contains apolipoprotein (apo) E as its only protein component, has been proposed to play a role in cellular cholesterol efflux by acting, like pre-beta1-LpA-I, as an initial acceptor of cell-derived cholesterol. In order to further characterize the presence of gamma-LpE in human plasma, we have separated gamma-LpE by two-dimensional non-denaturing polyacrylamide-gradient gel electrophoresis and detected its presence by immunoblotting with 125I-labeled polyclonal anti-apoE antibody. Five species of gamma-LpE were routinely detected in human plasma, ranging in mean particle diameter from 9.5 to 16.5 nm. The largest proportion of gamma-migrating apoE was associated with gamma-LpE having a diameter of 13.0 nm. Neither the amount of gamma-LpE apoE (representing less than 1-2% of total plasma apoE) nor the number of gamma-LpE subfractions was different in serum vs. plasma, or was affected by the presence of agents able to inhibit protein dimerization. Gamma-LpE subfractions were present in the plasma of patients having different apoE phenotypes (i.e., apoE 2/2, 3/3, or 4/4). Incubation of plasma at 37 degrees C (90 min) caused a significant decrease in plasma gamma-LpE (>80%) that was not dependent on LCAT or CETP activity. Storage (at -70 degrees C) of hypertriglyceridemic but not normolipidemic plasma resulted in an increase in gamma-LpE. Freezing of postprandial plasma samples, containing increased amounts of triglyceride-rich lipoproteins (TRL) enriched in apoE, also caused an increase in gamma-LpE. Incubation of VLDL (d < 1.006 g/ml) with lipase resulted in the production of gamma-migrating apoE. These results demonstrate that: 1) different gamma-LpE subfractions exist in human plasma; 2) the amount of apoE associated with gamma-LpE subfractions is dependent on in vitro conditions of plasma storage; and 3) TRL can act as a source of gamma-LpE apoE in vitro.

Adult↗
PubMed1998

Postprandial lipemia: emerging evidence for atherogenicity of remnant lipoproteins.

Patients with coronary artery disease (CAD) often have increased postprandial triglyceride levels compared with healthy control subjects, and it has been demonstrated that plasma triglyceride concentration in the fed state is an independent predictor of CAD. Increased postprandial triglyceridemia is strongly associated with a constellation of potentially atherogenic and thrombogenic lipoprotein changes, including a) increase in the plasma concentration of intestinally derived chylomicrons and their remnants; b) increase in the level of hepatic very low density lipoproteins and their remnants; c) decrease in level of high density lipoprotein (HDL) cholesterol because of increase in cholesteryl transfer from HDL to postprandial triglyceride-rich lipoproteins (TRL); d) decrease in low density lipoprotein (LDL) size, associated with increased susceptibility of LDL to oxidation; and e) increase in the association of lipoprotein (a) with TRL. Postprandial TRL are potentially thrombogenic because they are associated with increased activated factor VII activity (a procoagulant effect) and increased levels of plasminogen activator inhibitor-1 (an antifibrinolytic effect). Experimental results and clinical trial data suggest that plasma accumulation of remnant lipoproteins (in the fed or fasted state) is not just an associated feature of an atherogenic lipoprotein profile but that TRL remnants themselves contribute to the pathogenesis of atherosclerosis. Diet and/or drug treatments that lower the level of TRL in the fasted state also tend to have a beneficial effect on postprandial lipoprotein levels. Thus, aerobic exercise, weight reduction and triglyceride-lowering medications all reduce postprandial triglyceridemia and have the potential to reduce the level of atherogenic remnant lipoproteins.

Arteriosclerosis↗
PubMed1998

Association of apolipoprotein E with alpha2-macroglobulin in human plasma.

Apolipoprotein (apo) E plays a central role in the transport of lipids among different organs and cell types, whereas alpha2-macroglobulin (alpha2M) is responsible for the binding and inactivation of plasma proteases, as well as the transport of various cytokines, growth factors, and hormones. In the present study, evidence is presented for direct binding of apoE with alpha2M in human plasma, based on the observation that two-dimensional non-denaturing gradient gel electrophoretic separation of plasma resulted in co-migration of apoE with alpha2M in a complex intermediate in size (18.5 nm in diameter) between low (LDL) and high density lipoproteins (HDL). ApoE associated with alpha2M could be immunoprecipitated from plasma with anti-human alpha2M antiserum. Purified apoE, labeled with 125I, bound to native and methylamine-activated alpha2M (alpha2M-MA) in vitro in a time- and concentration-dependent manner. ApoE bound to alpha2M-MA with greater affinity than alpha2M. The binding of apoE to both alpha2M and alpha2M-MA did not depend on the presence of lipid. Ingestion of an oral fat load resulted in a reduction in the amount of apoE associated with alpha2M. Sphingomyelin vesicles and very low density lipoproteins (VLDL), but not phosphatidylcholine vesicles or HDL3, inhibited the in vitro binding of 125I-labeled apoE3 to alpha2M and alpha2M-MA. Binding of 125I-labeled apoE3 was also partially inhibited by an excess of platelet-derived growth factor and beta-amyloid protein, but not interferon-gamma. Subjects with an apoE 4/4 phenotype had less apoE associated with alpha2M in plasma than subjects with an apoE 3/3 or 2/2 phenotype, corresponding to reduced in vitro binding of apoE4 with alpha2M or alpha2M-MA. Although the functional significance of apoE binding to alpha2M remains to be determined, the present results demonstrate that: 1) apoE is non-covalently bound to alpha2M in human plasma, 2) alpha2M-MA has a greater capacity to bind apoE than alpha2M, 3) various proteins or lipoproteins known to bind apoE or alpha2M can potentially affect the interaction of apoE with alpha2M, and 4) association of apoE with alpha2M or alpha2M-MA is dependent on apoE phenotype.

Apolipoproteins E↗
PubMed1997

Pseudo type III dyslipoproteinemia is associated with normal fibroblast lipoprotein receptor activity.

Pseudo type III (PT-III) dyslipoproteinemia is characterized by a plasma accumulation of triglyceride-rich lipoproteins (TRL) and their remnants. It mimics type III, but its etiology can not be ascribed to a genetic apo E defect. In order to determine whether PT-III is associated with a genetic lipoprotein receptor abnormality, we have measured (in cultured fibroblasts from affected and nonaffected individuals) the in vitro activity of three lipoprotein receptors which are implicated in the catabolism of TRL, namely the low-density lipoprotein receptor (LDL-R), the lipoprotein receptor-related protein (LRP) and the lipolysis-stimulated receptor (LSR). Specific cell association and degradation of 125I-LDL by LDL-R-upregulated PT-III fibroblasts was not significantly different from that of control cells (103 +/- 10% and 98 +/- 17% of controls; 20 microg/ml 125I-LDL). Specific cell association and degradation of rabbit 125I-beta-VLDL was also not significantly different. LRP activity was assessed by measuring the ability of PT-III and control cells to bind three different LRP ligands: activated alpha2-macroglobulin (alpha2M-MA), lactoferrin and apo E-enriched rabbit beta-VLDL. No significant differences were observed (24.0 +/- 2.1 vs. 23.4 +/- 5.7 fmol/mg for 5 nM of 125I-alpha2M-MA; 4.8 +/- 0.3 vs. 5.2 +/- 1.3 microg/mg for 20 microg/ml of 125I-lactoferrin; 319.4 +/- 51.2 vs. 309.5 +/- 23.2 ng/mg for 5 microg/ml of 125I-beta-VLDL, PT-III vs. control, respectively). LSR activity, as assessed by the cell association or degradation of 125I-LDL by fibroblasts in the presence of 0.5 mM oleate and human leptin, was also not different. No evidence was obtained for deficient cellular recognition of PT-III TRL (d < 1.006 g/ml) by normal human fibroblasts or mouse macrophages. These results suggest that PT-III dyslipoproteinemia is not due to an accumulation in plasma of poorly recognized TRL, nor due to a genetic defect in LDL-R, LRP or LSR.

Animals↗
PubMed1997

Association of Lp(a) rather than integrally-bound apo(a) with triglyceride-rich lipoproteins of human subjects.

The majority of apolipoprotein (a) [apo(a)] in plasma is characteristically associated with Lipoprotein (a) [Lp(a)], having a buoyant density (1.05-1.08 g/ml) intermediate between low density lipoproteins (LDL) and high density lipoproteins (HDL). In the fed (postprandial) state or in the presence of fasting (endogenous) hypertriglyceridemia, a small proportion of plasma apo(a) is found in the density < 1.006 g/ml fraction of plasma, associated with larger and less dense triglyceride-rich lipoproteins (TRL). In order to further characterize the presence of apo(a) in ultracentrifugally-separated TRL (UTC-TRL), this lipoprotein fraction was isolated from plasma obtained in the fed state (three hours after an oral fat load) from healthy normolipidemic subjects (Lp(a): 38 +/- 8 mg/dl (mean +/- S.E.), n = 4) and also from plasma obtained after an overnight fast from hypertriglyceridemic patients (plasma TG: 8.16 +/- 2.00 mmol/l, Lp(a): 41 +/- 3 mg/dl, n = 18). Apo(a) in 3 h-postprandial UTC-TRL (5 +/- 2% of total plasma apo(a)) and in hypertriglyceridemic UTC-TRL (8 +/- 2% total apo(a)) was separable by electrophoresis and/or gel chromatography (FPLC) from the majority of UTC-TRL lipid. Apo(a) in UTC-TRL fractions had slow pre-beta electrophoretic mobility and was isolated in a lipoprotein size-range smaller than VLDL and larger than LDL, consistent with it being Lp(a). Recentrifugation of UTC-TRL resulted in the majority of apo(a) being recovered in the density > 1.006 g/ml fraction. Addition of proline to plasma samples before ultracentrifugation (final concentration: 0.1 M) substantially reduced the amount of Lp(a) in UTC-TRL. TRL separated from plasma by FPLC contained less apo(a) (2-5% of total plasma apo(a)), but this apo(a) was also readily dissociable from TRL lipid, had slow pre-beta electrophoretic mobility, and was associated with a lipoprotein with the size of Lp(a). Our data suggest that apo(a) in the TRL fraction of subjects with postprandial triglyceridemia or endogenous hypertriglyceridemia is not an integral component of plasma VLDL or chylomicrons, but represents the presence of non-covalently bound Lp(a).

Adult↗
PubMed1997

Prevalence of double pre-beta lipoproteinemia in hyperlipidemic patients is influenced by gender, menopausal status, and ApoE phenotype.

Double pre-beta lipoproteinemia (DPBL) is a plasma lipoprotein phenotype characterized by the presence of two agarose gel electrophoretic populations of very low density lipoproteins (VLDLs, d < 1.006 g/mL), i.e., normal pre-beta-migrating VLDL and slow pre-beta VLDL. Slow pre-beta VLDL represents remnant lipoproteins derived from the hydrolysis of triglyceride (TG)-rich lipoproteins (TRLs), and thus DPBL is a characteristic of plasma remnant lipoprotein accumulation. To determine the prevalence of DPBL in our lipid clinic population, patients (n = 2501) were selected who (1) had an unambiguous VLDL electrophoretic phenotype and could be classified as having either DPBL (DPBL+), beta-migrating VLDL (beta-VLDL +), or an absence of both (DPBL/beta-VLDL-/-) and (2) had hypercholesterolemia (HC: plasma cholesterol > or = 6.2 mmol/L, n = 1017), hypertriglyceridemia (HTG: plasma TG > or = 2.3 mmol/L but < 15 mmol/L, n = 554) or combined hyperlipidemia (HC + HTG, n = 930). Patients with TG < 2.3 mmol/L and cholesterol < 5.2 mmol/L acted as control subjects (n = 343). Using a commercially available agarose gel electrophoresis system, we identified 220 hyperlipidemic patients (8.8%) with DPBL (versus < 1% of control). The prevalence of DPBL was higher in (1) male than in female patients (10.7% versus 6.7%), (2) postmenopausal than in premenopausal females (7.3% versus 4.1%), and (3) patients with HC + HTG than in those with HTG or HC alone (15.8% versus 8.3% versus 2.7%, respectively). Patients with an epsilon 2 allele had a higher prevalence of DPBL; i.e., 26.9% of apoE 3/2 and 26.2% of apoE 4/2 patients had DPBL compared with 6.5%, 6.8%, and 7.4% of apoE 3/3, 4/3, and 4/4 patients, respectively. DPBL patients consistently had increased levels of VLDL-C and (LDL + HDL)-TG and decreased levels of LDL-C, and their plasma lipid profiles were intermediate between those of beta-VLDL+ and DPBL/beta-VLDL -/- patients. These results demonstrate that male sex, postmenopausal status in women, and the presence of an apoE 3/2 or apoE 4/2 phenotype are associated with an increased incidence of DPBL in hyperlipidemic patients.

Adult↗
PubMed1997

Characterization of human plasma apolipoprotein E-containing lipoproteins in the high density lipoprotein size range: focus on pre-beta1-LpE, pre-beta2-LpE, and alpha-LpE.

We have used two-dimensional gel electrophoresis to separate and characterize human plasma apolipoprotein (apo) E-containing lipoproteins in the high density lipoprotein (HDL) size range. Lipoproteins were separated from whole plasma by electrophoresis (according to charge) in a 0.75% agarose gel, and then in the second dimension (according to size) in a 2-15% non-denaturing polyacrylamide gradient gel. ApoE-containing lipoproteins were detected by radiography after electrotransfer of lipoproteins to nitrocellulose membranes and incubation with 125I-labeled affinity-purified polyclonal apoE antibody. ApoE-containing lipoproteins in the HDL size range had a particle size ranging from 9 to 18.5 nm in diameter and could be characterized as having either gamma, pre-beta1-, pre-beta2- or alpha-electrophoretic mobility (designated gamma-LpE, pre-beta1-LpE, pre-beta2LpE, and alpha-LpE respectively). gamma-LpE and a substantial proportion of pre-beta1- and pre-beta2-LpE did not co-migrate with apoA-I, apoA-II, apoC-III, or apoB-100. Subsequent experiments focused on the pre-beta1-LpE, pre-beta2LpE, and alpha-LpE subfractions, which represented > 95% of apoE in HDL-sized lipoproteins. Storage of plasma at 4 degrees C or in vitro incubation of plasma at 37 degrees C caused a relative decrease in pre-beta1-LpE and increase in alpha-LpE. Normolipidemic patients with an apoE 2/2 phenotype tended to have increased levels of alpha-LpE, whereas apoE 4/4 subjects tended to have a greater proportion of HDL-apoE as pre-beta1-LpE. Decrease in plasma HDL apoE concentration after an oral fat load was associated with a reduction in the plasma concentration of all HDL-apoE subfractions. These results demonstrate that: 1) apoE-containing HDL are heterogeneous in size and charge; 2) pre-beta1-LpE is a relatively labile HDL subfraction; 3) HDL-apoE subfraction distribution is dependent on apoE phenotype; and 4) all apoE-containing HDL subfractions participate in the plasma transfer of apoE during the postprandial period.

Adult↗
PubMed1997

Plasma lipoprotein distribution of apoC-III in normolipidemic and hypertriglyceridemic subjects: comparison of the apoC-III to apoE ratio in different lipoprotein fractions.

In order to assess the relationship between plasma accumulation of triglyceride-rich lipoproteins (TRL) and lipoprotein levels of apoC-III and apoE, we have measured apoC-III and apoE in lipoproteins separated according to size (by automated gel filtration chromatography) from plasma of normolipidemic subjects (plasma triglyceride (TG): 0.84 +/- 0.10 mmol/l; mean +/- SE, n = 8), and from type III (n = 8) and type IV (n = 8) hyperlipoproteinemic patients, matched for plasma TG (5.76 +/- 0.62 v 5.55 +/- 0.45 mmol/l, resp.). Total plasma apoC-III concentration was similar in type III and type IV patients (33.1 +/- 3.4 v 37.6 +/- 4.4 mg/dl, respectively), but was significantly increased compared to normolipidemic controls (10.0 +/- 1.0 mg/dl, P < 0.001). TRL apoC-III was lower and high density lipoprotein (HDL) apoC-III was significantly higher in type III versus type IV subjects (14.8 +/- 3.2 vs. 22.8 +/- 3.0 mg/dl, P < 0.05; 8.3 +/- 1.0 vs. 5.2 +/- 0.5 mg/dl, P < 0.05). Plasma concentration of apoC-III in lipoproteins that eluted between TRL and HDL (intermediate-sized lipoproteins, ISL) was similar in the two hypertriglyceridemic groups (10.1 +/- 1.3 vs. 9.7 +/- 1.6 mg/dl), but was significantly higher (P< 0.05) than controls (2.2 +/- 0.3 mg/dl). TRL, ISL, and HDL apoE concentrations were significantly higher in type III versus type IV subjects (P < 0.05). All lipoprotein fractions in type III patients were characterized by lower apoC-III to apoE ratios. In contrast, the TRL apoC-III to apoE ratio of type IV patients was similar and the ISL apoC-III to apoE ratio was significantly higher, compared to normolipidemic individuals. These results indicate that compared to normolipidemic individuals, remnant-like lipoproteins in the ISL fraction of type IV patients are enriched in apoC-III relative to apoE, whereas those of type III patients are enriched in apoE relative to apoC-III.

Adult↗
PubMed1996

Triglycerides: a risk factor for coronary heart disease.

Multiviriate analysis of epidemiological data has often shown that elevated plasma triglyceride (TG) concentration is not an independent risk factor for coronary heart disease (CHD). However, more recently, subgroup- and meta-analyses have supported an independent association between TG and CHD. The strength of TG to predict the CHD lies in its ability to reflect the presence of atherogenic plasma TG-rich lipoprotein (TRL) remnants. Clinical evidence for the potential atherogenicity of TRL is provided by patients with type III hyperlipoproteinaemia, hepatic lipase deficiency or apolipoprotein E deficiency, who have marked increase in plasma remnant lipoproteins and an increased incidence of CHD. Indirect evidence suggests that the presence of a single epsilon 2 allele may have atherogenic potential by influencing plasma remnant accumulation in the presence of a second environmental or genetic factor. Recent studies have also indicated that the magnitude of postprandial triglyceridaemia is a significant predictor of CHD. Emerging data from angiographic intervention trials have implicated TRL in atherosclerotic disease progression independently of low-density lipoproteins (LDL). Thus, in hypertriglyceridaemic patients, physicians should conduct a thorough clinical evaluation, a family survey, an assessment of associated risk factors and a complete analysis of the plasma lipoprotein profile, in order to assess the atherogenic potential of this hyperlipidaemia.

Animals↗
PubMed1996

Plasma concentration of apolipoprotein E in intermediate-sized remnant-like lipoproteins in normolipidemic and hyperlipidemic subjects.

Triglyceride-rich lipoprotein (TRL) remnants have been strongly implicated in the pathogenesis of atherosclerosis. To further investigate plasma remnant lipoprotein metabolism, we have determined the plasma concentration of apolipoprotein (apo) E (by polyclonal enzyme-linked immunoassay) in remnant-like lipoproteins, isolated by automated gel filtration chromatography as a fraction intermediate in size between VLDL and HDL. In normolipidemic subjects (n = 12), 1.2 +/- 0.11 mg/dL (33 +/- 2%, mean +/- SE) of total plasma apoE was associated with this fraction (termed ISL apoE). In hypercholesterolemic (type IIa, n = 12), hypertriglyceridemic (type IV, n = 12), and mixed hyperlipidemic (type IIb, n = 12) subjects, mean ISL apoE concentrations were 2.1 +/- 0.2, 2.5 +/- 0.2, and 3.8 +/- 0.4 mg/dL, respectively (P < .001 versus normal values) (45 +/- 2%, 32 +/- 2%, and 44 +/- 2% of total). ISL apoE was 8.7 +/- 1.4 mg/dL (42 +/- 3%) in type III dyslipidemic subjects (apoE2/2, n = 8). ISL apoE was positively correlated with plasma triglyceride (r = .41, P < .01), and at any given level of plasma triglyceride, subjects with an apoE2/2 or apoE3/2 phenotype tended to have a higher concentration of ISL apoE (P < .01) than apoE3/3 or E4/3 individuals. ISL apoE was also correlated (P < .001) with total plasma cholesterol (r = .66), TRL cholesterol (r = .49), TRL apoE (r = .47), LDL apoB (r = .42), and LDL+HDL triglyceride (r = .74). These results suggest that (1) a significant proportion of plasma apoE resides within an intermediate-sized remnant-like lipoprotein fraction in both normolipidemic and hyperlipidemic subjects; (2) plasma remnant lipoprotein accumulation is associated with an elevation in ISL apoE concentration; and (3) ISL apoE concentration is significantly correlated with various proatherogenic lipid parameters and may itself be a potentially important atherogenic index.

Adult↗
PubMed1995

Clustering of cardiovascular risk factors: targeting high-risk individuals.

Cardiovascular risk factors have traditionally been divided into 2 categories: modifiable risk factors (smoking, hypertension, elevated cholesterol, reduced high density lipoprotein cholesterol, and diabetes), and nonmodifiable risk factors (age, gender, and hereditary factors). However, more recent data indicate clustering of several metabolic and familial factors that are often related to each other. A pattern of lipoprotein abnormalities characterized by increased hepatic production of apolipoprotein B-containing lipoprotein particles, high blood pressure, visceral obesity, and peripheral insulin resistance are identified with increasing frequency in subjects with premature coronary artery disease (CAD). The metabolic substrates for many such disorders are being uncovered, and genetic analysis of affected kindred have, often with conflicting results, suggested associations with candidate genes. In the context of a multifactorial approach, aggressive treatment of lipoprotein disorders in high-risk individuals, or in the secondary prevention of cardiovascular diseases, has resulted in a decreased rate of progression of CAD and a marked reduction in clinical events. Further work in the field of hemostatic factors has shown that fibrinogen, activated coagulation factor VII, spontaneous platelet aggregation, and elevated levels of plasminogen activator inhibitor-1 (PAI-1), are all associated with CAD. There is a strong association between lipids (especially triglyceride-rich lipoproteins) and fibrinogen, PAI-1, and activation of factor VII. In addition, vascular function, especially endothelial cell physiology, has been shown to be compromised in the presence of multiple risk factors and to be improved with intensive therapy aimed at reducing risk factors, especially plasma lipoprotein levels. The implications for clinical practice are important. In the primary prevention of cardiovascular disease, proper risk stratification must be carried out with specific attention given to lifestyle changes. Cessation of smoking and changes in diet (both qualitative and quantitative), exercise, and serenity are often required. In the prevention of cardiovascular disease in subjects at high risk, or in the secondary prevention of CAD, a clear justification exists for aggressive lifestyle changes, often coupled with lipid-lowering therapy and adequate blood pressure control. Basic research is providing us with a better understanding of the molecular interactions between lipoproteins and hemostatic factors. It is becoming increasingly necessary to develop novel pharmaceutical agents with the combined ability to reduce atherogenic lipoprotein levels while also reducing susceptibility to thrombosis.

Adult↗
PubMed1995

Impact of age on the metabolism of VLDL, IDL, and LDL apolipoprotein B-100 in men.

Levels of plasma very low density lipoprotein (VLDL) and low density lipoprotein (LDL) constituents increase with age. In an attempt to further define the mechanisms responsible for these changes, kinetic studies of VLDL and LDL apolipoprotein (apo) B-100 were carried out in 19 normolipidemic male subjects with plasma total cholesterol and triglyceride levels below the 90th percentile whose ages ranged from 24 to 73 years. Subjects were maintained on standardized diets consisting of 47-49% of calories as carbohydrate, 15% protein, and 36-40% fat (15-17% saturated, 15-17% monounsaturated, 6% polyunsaturated) with 150 mg cholesterol/1000 kcal. At the end of the diet period, the metabolism of apoB-100 within VLDL, intermediate density lipoprotein (IDL), and LDL was studied in the fed state using a primed-constant infusion of [2H3]leucine. Data were fit to a multicompartmental model to determine residence times and production rates of apoB-100 in each fraction. There were significant positive correlations between age and VLDL, IDL, and LDL apoB-100 concentrations (r = 0.50, 0.62, and 0.69; P = 0.03, 0.004, and 0.001, respectively). There was a positive correlation between age and the production rate of VLDL apoB-100 (r = 0.50, P = 0.03), but there was no significant relationship between age and either IDL or LDL apoB-100 production rates. Age was also positively correlated with the residence time of LDL apoB-100 (r = 0.68 P = 0.001). Our data suggest that the age-associated increase in VLDL apoB-100 is due to an increased production rate of this constituent, whereas the age-associated increase in LDL apoB-100 is due to an increased residence time of these particles in plasma.

Adult↗
PubMed1994

Postprandial lipid metabolism.

Several studies have shown that patients with coronary artery disease have an elevated plasma triglyceride response to a fat-rich meal. Recent evidence suggests that postprandial triglyceridemia is in fact an independent predictor of coronary and carotid atherosclerosis. In order to further characterize postprandial lipid metabolism, recently published studies have investigated the role of liver-derived lipoproteins in determining the magnitude of postprandial triglyceridemia, and have further defined the effect of glucose intolerance and lipid-lowering drugs on postprandial plasma lipoprotein parameters.

Arteriosclerosis↗
PubMed1994

A unique approach to multi-state networking: BHSL (Basic Health Sciences Network).

Development of a reciprocal multi-state shared resources network is described. The Basic Health Sciences Library Network (BHSL) is one the largest interlibrary loan networks free of direct charges to participants and any direct federal or state funding. Established in June 1986, BHSL started with 132 member libraries from three northeastern states. Current membership is 460 libraries in 10 states. Interlibrary loan activity for 1992 resulted in a collective cost savings of $592,672. This model of resource sharing can be applied to any group of libraries that access a common locator tool.

Cost Savings↗
PubMed1993

Contribution of apoB-48 and apoB-100 triglyceride-rich lipoproteins (TRL) to postprandial increases in the plasma concentration of TRL triglycerides and retinyl esters.

After the ingestion of a fat-rich meal, there is a postprandial increase in the plasma concentration of both apolipoprotein B-48- and apoB-100-containing triglyceride-rich lipoproteins (apoB-48 and apoB-100 TRL). In order to determine the contribution of these lipoproteins to postprandial lipemia, the concentration of triglycerides (TG) and retinyl esters (RE) was measured in apoB-48 and apoB-100 TRL after an oral fat load. Six normolipidemic male subjects were fed heavy cream (1 g fat per kg body weight) containing vitamin A (3000 retinol equivalents). TRL were isolated by ultracentrifugation from plasma samples obtained at regular intervals after the meal, and apoB-100 TRL were separated from apoB-48 TRL by affinity chromatography using monoclonal antibodies. Postprandial increase in plasma TG concentration was due to an increase in TG in the TRL fraction, which in turn was predominantly (82 +/- 4%) due to an increase in TG in apoB-48 TRL. Contribution of apoB-100 TRL to postprandial increase in TRL TG was 3-27% in individual subjects. ApoB-100 TRL remained a significant carrier of total plasma triglyceride in the fed state, as reflected by similar apoB-100 and apoB-48 TRL TG concentrations at 2, 4, and 6 h after the fat meal. Retinyl esters were regularly detected in apoB-100 TRL. Seventy-five (+/- 9) percent of the increase in TRL-RE was due to RE in apoB-48 TRL and 25 +/- 9% was due to RE in apoB-100. These data suggest that RE in plasma are not always associated with apoB-48-containing lipoproteins.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1991

Plasma lipoprotein distribution of apolipoprotein(a) in the fed and fasted states.

In order to quantitate the contribution of triglyceride-rich lipoprotein (TRL) apolipoprotein(a) to total plasma apo(a) concentration in the fed and fasted states, we have studied a group of 20 male subjects (age 49 +/- 3 years) with fasting apo(a) concentrations varying from 39 to 1385 U/l. After a 12-h overnight fast, each subject was given a fat-rich meal (1 g fat/kg body weight) and venous blood samples were obtained at hourly intervals for 10 h. TRL were isolated from bihourly plasma samples by ultracentrifugation (d less than 1.006 g/ml) and apo(a) was measured by radioimmunoassay. Total plasma apo(a) concentration did not change after the meal. However, TRL apo(a) increased significantly (0 h: 3 +/- 1, 4 h: 30 +/- 7 U/l; p less than 0.001) and 'd greater than 1.006' apo(a) decreased (0 h: 267 +/- 56, 4 h: 231 +/- 50 U/l; P less than 0.05). Similar postprandial changes were observed in apoB concentration (TRL apo B at 0 h: 10.3 +/- 1.5, 4 h: 13.6 +/- 1.7 g/l, P less than 0.001, 'd greater than 1.006' apoB at 0 h: 118 +/- 7, 4 h: 110 +/- 7 g/l, P less than 0.001). In the fasted state 2.0 +/- 1.0% and in the fed state (4 h postprandially) 16.0 +/- 4.6% of total plasma apo(a) was found in the TRL fraction. Eleven subjects had less than 10% of total apo(a) in TRL, 5 had 25% or more apo(a) in TRL in the fed state. Postprandial increase in TRL apo(a) was significantly correlated (r = 0.75, P less than 0.001) with increase in plasma triglycerides. TRL apo(a) concentration in the fed state was not correlated with total fasting cholesterol, triglyceride, apo(a) or HDL cholesterol concentration. We conclude that in some individuals, TRL apo(a) makes a significant contribution to total plasma apo(a) concentration in the fed state.

Adult↗