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PubMed2002

Different effects of diets rich in olive oil, rapeseed oil and sunflower-seed oil on postprandial lipid and lipoprotein concentrations and on lipoprotein oxidation susceptibility.

Elevated concentrations of fasting and non-fasting triacylglycerol-rich lipoproteins (TRL) as well as oxidative changes of lipoproteins may increase the risk of ischaemic heart disease. To compare the effects of different diets rich in unsaturated fatty acids on the concentrations and in vitro oxidation of fasting and postprandial lipoproteins eighteen males consumed diets enriched with rapeseed oil (RO), olive oil (OO), or sunflower-seed oil (SO) in randomised order for periods of 3 weeks followed by a RO test meal. In the postprandial state the concentrations of cholesterol and triacylglycerol (TAG) in TRL were higher after consumption of OO compared with RO and SO (P<0.04), possibly related to differences in the fasting state. The propagation rates for VLDL and LDL oxidation were higher in the postprandial compared with the fasting state irrespective of diet. In the fasting state, the propagation rates were highest after SO (P<0.001), and in the postprandial state, SO gave rise to a shorter VLDL lag time (P=0.03) and a higher propagation rate than OO consumption (P=0.04). Overall, the SO diet resulted in a higher postprandial propagation rate of LDL (P<0.001) compared with RO and OO, while there was no effect of diet on LDL oxidation lag time. Our results suggest that RO and SO diets lower the postprandial cholesterol and TAG concentrations compared with OO, while RO and OO diets result in similar and lower in vitro susceptibility to oxidation of lipoproteins than SO.

Adult↗

PubMed1977

Supplementation with vitamin E in hyperlipidemic patients treated with diet and clofibrate. Effects on serum lipoprotein concentrations, plasma fatty acid composition and adipose tissue lipoprotein lipase activity.

Twelve hyperlipidemic patients on long term treatment with a lipid lowering diet enriched in polyunsaturated fatty acids and with clofibrate were supplemented with vitamin E (400 mg/day). The effect on serum lipoprotein concentration, plasma lipid fatty acid composition, and adipose tissue lipoprotein lipase activity was studied. No additional lipid-lowering effect was registered during a treatment period of 4 months. A slight increase in total serum cholesterol concentration and in high density lipoprotein concentration was probably attributable to seasonal variations in serum lipoprotein concentrations. No major changes of fatty acid composition in plasma cholesteryl esters or triglycerides were recorded. However, an increased relative amount of arachidonic acid and a reduced amount of palmitic acid in the plasma phospholipids after 2 months was possibly caused by the vitamin E therapy.

Adipose Tissue↗

PubMed1992

Lipoprotein-containing apolipoprotein A-I: sex-related quantitative and qualitative changes in this lipoprotein subspecies after ingestion of fat.

We investigated the postprandial changes of two species of lipoproteins containing apolipoprotein (apo)A-I: lipoprotein containing apo A-I but no apo A-II (LpA-I), and lipoprotein containing apo A-I and apo A-II (LpA-I/A-II). These lipoproteins were isolated from 10 men and 11 women at 0, 4, and 6 h after they had eaten butter. In LpA-I, the concentrations of all lipids except triglyceride were increased at 4 and 6 h in the women. In the men all lipids were increased only at 4 h. The increase of apo A-I concentration was found at 6 h only in the women. In LpA-I/A-II, the concentrations of all lipids were increased at 4 h and only phospholipid (PL) was increased at 6 h in the women. In the men, free cholesterol and PL were increased at 4 and 6 h. The increases of apo A-I and apo A-II concentrations were found at 4 and 6 h only in the men. These results suggest that the postprandial changes are sex-related and may relate to the different incidence of atherosclerotic cardiovascular disorders.

Adult↗

PubMed1997

Stearic acid, trans fatty acids, and dairy fat: effects on serum and lipoprotein lipids, apolipoproteins, lipoprotein(a), and lipid transfer proteins in healthy subjects.

To compare the effects on serum lipoproteins of stearic acid, trans fatty acids, and dairy fat, 80 healthy subjects consumed a dairy fat-based (baseline) diet for 5 wk, then an experimental diet high in either trans fatty acids (8.7% of energy; n = 40) or stearic acid (9.3% of energy; n = 40) for another 5 wk. All diets provided 32.2-33.9% of energy as fat, 14.6-15.8% as saturated plus trans fatty acids, 11.4-12.5% as cis-monounsaturated fatty acids, 2.9-3.5% as polyunsaturated fatty acids, and 200-221 mg cholesterol/10 MJ. Compared with the dairy fat diet, stearic acid and trans fatty acids decreased serum total cholesterol concentrations similarly (by 13% and 12%, respectively, P < 0.001) but the trans fatty acid diet decreased HDL cholesterol (17%) and apolipoprotein (apo) A-I (15%) significantly more than did the stearic acid diet (11% and 12%, respectively). Stearic acid but not trans fatty acids reduced concentrations of LDL cholesterol and apo B significantly (P < 0.001). The trans fatty acid diet increased the ratio of LDL to HDL cholesterol (19%) and of apo B to apo A-I (16%) more than did the dairy fat diet (P < 0.001) but the stearic acid diet had no effect. Lipoprotein(a) concentrations increased with both experimental diets, significantly more with trans fatty acids (30%) than with stearic acid (10%). In conclusion, high amounts of trans fatty acids had more adverse effects on lipoproteins than did equal amounts of stearic acid and dairy fat. Stearic acid reduced LDL cholesterol, did not affect the ratio of LDL to HDL cholesterol, and increased lipoprotein(a), although to a lesser extent than did trans fatty acids. Dietary fats low in both saturated fatty acids and trans fatty acids should be favored.

Adult↗

PubMed1985

Binding of high-density lipoproteins to luteal membranes: the role of prolactin, luteinizing hormone, and circulating lipoproteins.

Ovarian and adrenal membranes from immature gonadotropin-primed rats, treated with 4-amino-pyrazolopyrimidine (4APP) to reduce endogenous lipoprotein levels, displayed higher binding of porcine high-density lipoprotein (HDL) when compared to control rats. Immature, hypophysectomized (HYPOX) rats bearing corpora lutea (CL) on Day 5 after ovulation had lower levels of serum progesterone and reduced capacity for HDL and human chorionic gonadotropin (hCG) binding to ovarian membranes when compared with intact animals. Hypophysectomy also reduced the number of HDL binding sites in adrenal membranes. Treatment of HYPOX animals with luteinizing hormone (LH) and prolactin (Prl) alone or in combination increased the HDL binding sites in the ovary relative to HYPOX-untreated rats. Neither hormone affected binding to adrenals, where only adrenocorticotropic hormone (ACTH) enhanced HDL binding. LH treatment reduced the serum progesterone levels and hCG binding to the ovaries, whereas Prl administration increased progesterone levels with no effect on hCG binding. We conclude from this study that HDL binding in the luteinized ovary is regulated by Prl and LH and circulating lipoproteins, whereas in adrenals it is regulated by ACTH and circulating levels of lipoproteins.

Adenine↗

PubMed1994

The catabolism of apolipoprotein B from very low density lipoprotein and triglyceride-rich lipoprotein remnants in fasted septic rats.

The catabolism of apolipoprotein B (apo B) from very low density lipoproteins (VLDL) and triglyceride-rich lipoprotein (TRL) remnants in fasted control (C) and Escherichia coli-treated septic (S) rats was measured. In Experiment 1, [125I]VLDL was injected into rats from C and S groups. Blood was collected from 0 to 60 min postdose and apo B was isolated and counted for radioactivity. No significant difference in the half-life (t1/2) or fractional catabolic rate (FCR) of apo B was observed in the VLDL fraction. In Experiment 2, [125I]TRL remnants were injected into rats from C and S groups. Blood was collected from 0 to 90 min postdose and apo B isolated. The t1/2 was 2.5 times longer in the S compared with the C and the FCR was slower in the S rats. These experiments suggest that S rats do not clear triglyceride-rich lipoproteins as easily as normal-sized lipoproteins.

Animal Feed↗

PubMed1986

Binding of low-density lipoprotein and chylomicron remnants to the hepatic low-density lipoprotein receptor of dogs, rats and rabbits demonstrated by ligand blotting. Failure to detect a distinct chylomicron-remnant-binding protein by ligand blotting.

In this paper, human low-density lipoprotein (LDL), rat chylomicron remnants and very-low-density lipoproteins of beta-mobility from cholesterol-fed rabbits (beta VLDL) have been shown to bind strongly to a protein present in solubilised liver membranes of rats, rabbits and dogs by ligand blotting with biotin-modified lipoproteins. This binding protein was identified as the LDL-receptor on several criteria. First, binding of the lipoproteins to the receptor was saturable and Ca2+-dependent; secondly, the apparent relative molecular mass of the binding protein (ranging from 128,000 in the rabbit, 145,000 in the rat to 147,000 in the dog) was similar to that of the purified bovine LDL receptor. Finally, binding activity was greatly increased in the livers of rats treated with oestrogen in pharmacological doses and absent from the liver of Watanabe heritable hyperlipidaemic (WHHL) rabbits that have a genetic defect in the LDL receptor. Some binding was also observed to a high-molecular-mass protein present in solubilised liver membranes of rats and rabbits, which, in rabbits at least, shared antigenic determinants with rabbit apoB and was not likely to be related to the LDL receptor as it was present in equal amounts in normal and WHHL rabbits. No evidence was obtained for a specific chylomicron remnant binding protein, distinct from the LDL receptor, whose activity could be detected in solubilised liver membranes by ligand blotting although a variety of solubilisation and fractionation conditions were employed.

Animals↗

PubMed1996

Blockade of the alpha 2-macroglobulin receptor/low-density-lipoprotein-receptor-related protein on rat liver parenchymal cells by the 39-kDa receptor-associated protein leaves the interaction of beta-migrating very-low-density lipoprotein with the lipoprotein remnant receptor unaffected.

The nature of the liver binding site which is responsible for the initial recognition and clearance of chylomicron-remnants and beta-migrating very-low-density lipoprotein (beta-VLDL) is under active dispute. We have investigated the effect of the 39-kDa receptor-associated protein (RAP) on the recognition site for activated alpha 2-macroglobulin and beta-VLDL on rat liver parenchymal cells in vivo and in vitro in order to analyze whether both substrates are recognized and internalized by the same receptor system. Radiolabelled trypsin-activated alpha 2-macroglobulin (alpha 2M-T) was cleared rapidly by the liver (maximal uptake of 80.8 +/- 1.0% of the injected dose). Prior injection of 5, 15, or 50 mg gluthathione-S-transferase-linked RAP (GST-RAP)/kg rat reduced the liver uptake to 62.2 +/- 2.3%, 59.3 +/- 1.1%, or 2.9 +/- 0.1% of the injected dose, respectively. Concurrently the serum decay was strongly delayed after injection of 50 mg GST-RAP/kg rat but this did not affect the serum decay and liver uptake of 125I-beta-VLDL. Binding studies with isolated liver parenchymal cells in vitro demonstrated that the binding of 125I-alpha 2M-T was 98% inhibited by GST-RAP with an IC50 of 0.3 microgram/ml (4.2 nM), whereas the binding of 125I-beta-VLDL and 125I-beta-VLDL + recombinant apolipoprotein E (rec-apoE) was unaffected by GST-RAP up to 50 micrograms/ml (700 nM). Also, the cell association and degradation of alpha 2M-T was blocked by RAP, while the association and degradation of beta-VLDL and beta-VLDL + rec-apoE were not influenced. The inhibitory effect of RAP on the cell association and degradation of alpha 2M-T lasted for 1-2 h of incubation at 37 degrees C. The binding of the radioiodinated RAP to isolated liver parenchymal cells was highly efficiently coupled to lysosomal degradation. Upon in vivo injection into rats, 125I-labeled RAP is rapidly cleared from the serum and taken up by the liver, which is also coupled to efficient degradation. Since RAP blocks binding of all known ligands to the alpha 2-macroglobulin receptor/low-density lipoprotein receptor-related protein (the alpha 2Mr/LRP) and at high concentrations the binding to the LDL receptor, we conclude that the initial binding and internalization of beta-VLDL by rat liver parenchymal cells is not mediated by the alpha 2Mr/LRP. The properties of binding of beta-VLDL to rat liver parenchymal cells points to an apoE-specific recognition site for lipoprotein remnants which differs from the alpha 2Mr/LRP, proteoglycans and the LDL receptor and is tentatively called the lipoprotein remnant receptor.

Animals↗

PubMedDate not supplied

Lipoprotein(a) and apolipoprotein(a) in a New World monkey, the common marmoset (Callithrix jacchus). Association of variable plasma lipoprotein(a) levels with a single apolipoprotein(a) isoform.

In an earlier report (Chapman et al, Biochemistry 1979;18:5096-5108), we suggested that the common marmoset may represent an important model for the study of human plasma lipoprotein metabolism. We now extend the interest of this monkey model to the study of lipoprotein(a) (Lp[a]) and apolipoprotein(a) (apo[a]). Density gradient ultracentrifugal fractionation of marmoset plasma revealed a bimodal distribution of Lp(a), with one peak of concentration occurring in association with very low density lipoproteins (VLDLs) and a second in the density range 1.040-1.080 g/ml. The dense Lp(a) subspecies displayed physicochemical properties (chemical composition, particle size, and electrophoretic mobility) that closely resembled those of its counterpart in humans and baboons but that were distinct from those of low density lipoprotein (LDL). Furthermore, the particle size of marmoset Lp(a) was invariant (31 nm) over the density interval 1.040-1.080 g/ml, whereas that of LDL decreased progressively with an increase in density (approximately 26-25.2 nm). Use of polyclonal and monoclonal antibodies to human apo(a) and of a polyclonal antibody to marmoset Lp(a) allowed immunologic identification of a single apo(a) isoform in the marmoset whose size was similar to that of apo B-100; apo(a) and apo B-100 were associated in Lp(a) particles by a disulfide linkage. The total protein mass of apo-Lp(a) was estimated to be 800,000 or more by electrophoresis in sodium dodecyl sulfate-polyacrylamide-agarose gels. The amino acid compositions of marmoset and human apo(a) resembled each other but were distinct from those of the corresponding forms of apo B-100. Immunologic evidence is provided for a high degree of cross reactivity between apo(a) in marmosets, baboons, and humans, supporting the idea of the existence of a marked degree of structural homology between these proteins. In addition, electroimmunoblotting of marmoset apo(a) and marmoset plasminogen showed that these proteins shared certain epitopes in common, suggesting that marmoset apo(a) may possess kringle-like structural features. Finally, despite possession of a single apo(a) isoform, marmoset Lp(a) levels varied over a 100-fold range (0.5-49 mg/dl plasma). Considered together, our present findings suggest that the common marmoset monkey constitutes a unique model in which to study the regulation of apo(a) gene expression and the posttranslational processing of apo(a), as well as factors that modulate the synthesis, intravascular metabolism, and cellular catabolism of Lp(a).

Animals↗

PubMed1995

Lipoprotein lipase mass and activity in plasma and their increase after heparin are separate parameters with different relations to plasma lipoproteins.

Lipoprotein lipase (LPL) activity and mass in plasma and their increase after heparin administration were measured in 61 men who had suffered myocardial infarction before the age of 45 years and in 69 population-based age- and sex-matched control subjects without coronary heart disease to study the relations between these parameters in plasma and their correlations with plasma lipoproteins in subjects with a wide range of lipoprotein and LPL levels. There was a relatively large amount of LPL protein compared with LPL activity in preheparin plasma, indicating that the majority of circulating LPL is catalytically inactive. LPL mass and activity in postheparin plasma (postheparin minus preheparin values) were highly correlated, and the calculated mean specific activity (0.35 mU/ng) was in the range expected for catalytically active LPL. Hence, heparin releases mainly active LPL. The four LPL parameters (mass and activity in plasma and their increase after heparin administration) were not related to each other, except for postheparin plasma LPL mass and activity, and they showed different correlations with plasma lipoprotein lipid concentrations. There was a strong positive correlation between LPL mass in preheparin plasma and the HDL cholesterol level as well as weak negative relations to VLDL triglyceride and cholesterol concentrations in the patients. In contrast, preheparin LPL activity showed no correlation with the HDL cholesterol level but weak positive relations to VLDL triglyceride and cholesterol concentrations in the control subjects.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMedDate not supplied

Regulation of high density lipoprotein binding activity of aortic endothelial cells by treatment with acetylated low density lipoprotein.

High density lipoprotein (HDL) binding to human fibroblasts and arterial smooth muscle cells is up-regulated when sterol is delivered to cells in the form of nonlipoprotein cholesterol or low density lipoprotein (LDL). Results from the present study show that the HDL binding activity of aortic endothelial cells is up-regulated when cholesterol in the form of acetylated LDL (AcLDL) is delivered to cells via the "scavenger" lipoprotein receptor pathway. AcLDL treatment led to a dose-dependent, but saturable, increase in HDL binding to cultured bovine aortic endothelial cells that was reversed when cells were treated with lipoprotein-deficient serum. The AcLDL-mediated enhancement in HDL binding activity was inhibited by cycloheximide, suggesting the involvement of protein synthesis. This enhancement was associated with an increased cell cholesterol content, a suppressed rate of cholesterol synthesis, and an increased rate of cholesterol ester formation. Kinetic analysis of HDL binding showed that AcLDL treatment caused an increase in the apparent number of high-affinity binding sites (Kd approximately 3 micrograms/ml HDL protein). Competition and direct binding studies revealed that the inducible binding sites exhibited relative specificity for HDL over LDL and AcLDL. Thus, aortic endothelial cells appear to possess specific receptors for HDL that may function to facilitate HDL-mediated removal from cells of excess cholesterol internalized by the scavenger receptor pathway.

Animals↗

PubMed2003

Increased low-density lipoprotein oxidation and impaired high-density lipoprotein antioxidant defense are associated with increased macrophage homing and atherosclerosis in dyslipidemic obese mice: LCAT gene transfer decreases atherosclerosis.

BACKGROUND: Obesity-associated dyslipidemia in humans is associated with increased low-density lipoprotein (LDL) oxidation. Mice with combined leptin and LDL receptor deficiency are obese and show severe dyslipidemia and insulin resistance. We investigated the association between oxidation of apolipoprotein B-containing lipoproteins, high-density lipoprotein (HDL) antioxidant defense, and atherosclerosis in these mice. METHODS AND RESULTS: LDL receptor knockout (LDLR-/-), leptin-deficient (ob/ob), double-mutant (LDLR-/-;ob/ob), and C57BL6 mice were fed standard chow. Double-mutant mice had higher levels of non-HDL (P<0.001) and HDL (P<0.01) cholesterol and of triglycerides (P<0.001). They also had higher oxidative stress, evidenced by higher titers of autoantibodies against malondialdehyde-modified LDL (P<0.001). C57BL6 and ob/ob mice had no detectable lesions. Lesions covered 20% of total area of the thoracic abdominal aorta in double-mutant mice compared with 3.5% in LDLR-/- mice (P<0.01). Higher macrophage homing and accumulation of oxidized apolipoprotein B-100-containing lipoproteins were associated with larger plaque volumes in the aortic root of double-mutant mice (P<0.01). The activity of the HDL-associated antioxidant enzymes paraoxonase and lecithin:cholesterol acyltransferase (LCAT) (ANOVA; P<0.0001 for both) was lower in double-mutant mice. Adenovirus-mediated LCAT gene transfer in double-mutant mice increased plasma LCAT activity by 64% (P<0.01) and reduced the titer of autoantibodies by 40% (P<0.01) and plaque volume in the aortic root by 42% (P<0.05) at 6 weeks. CONCLUSIONS: Dyslipidemia and insulin resistance in obese LDL receptor-deficient mice are associated with increased oxidative stress and impaired HDL-associated antioxidant defense, evidenced by decreased paraoxonase and LCAT activity. Transient LCAT overexpression was associated with a reduction of oxidative stress and atherosclerosis.

Animals↗

PubMed1985

The ratio of plasma high-density lipoprotein cholesterol to total and low-density lipoprotein cholesterol: age-related changes and race and sex differences in selected North American populations. The Lipid Research Clinics Program Prevalence Study.

The distribution of the ratios of plasma high-density lipoprotein cholesterol (HDL-C) to total cholesterol (TC) and of HDL-C to low-density lipoprotein cholesterol (LDL-C) are presented for 6900 white and 495 black examinees greater than 4 years old. Measurements were obtained during the visit 2 survey of the Lipid Research Clinics (LRC) Program Prevalence Study, and correspond to a 15% random sample of 60,502 participants screened during the LRC visit 1 survey. Age-specific means, medians, and selected percentiles are given by sex and by gonadal hormone use in white women. Apparent in these cross-sectional data was a consistent age-related decline in the ratio of HDL-C to TC for white male participants, from a mean of 0.360 in the age group 5 to 9 to a mean of 0.211 in the age group 50 to 54. Thereafter the mean ratio increased slightly. In white women not using gonadal hormones the age-related decline in the ratio was only evident starting at the age group 35 to 39, from which it declines from 0.329 to 0.258 in the age group 55 to 59. White women using gonadal hormones showed very minor age-related changes in the HDL-C/TC ratio, varying around a mean of 0.300. The number of blacks examined was low and thus the racial comparisons must be interpreted with caution. For each gender, age-related trends were similar in black and white study participants. Black men, however, had a higher percentage of TC carried as HDL-C than white men in all age groups examined. Black women had a higher percentage of TC in HDL-C than white women only below age 20; in the adult age range no appreciable differences were seen. Pearson correlation coefficients between the lipid, lipoprotein, and lipoprotein ratios are presented. The ratio HDL-C/TC correlated highly with the ratio HDL-C/LDL-C (greater than 0.92 for all groups) and the former may be a more conveniently determined surrogate for the latter. Although not exhaustive regarding the information it conveys about a lipid pattern, the ratio HDL-C/TC has the advantage of summarizing complex associations into a single numerical approximation.

Adolescent↗

PubMed1999

Lipoprotein lipase mutations, plasma lipids and lipoproteins, and risk of ischemic heart disease. A meta-analysis.

BACKGROUND: We assessed in meta-analyses the effect of the Gly188Glu, Asp9Asn, Asn291Ser, and Ser447Ter substitutions in lipoprotein lipase in the heterozygous state on lipid metabolism and risk of ischemic heart disease (same order used below). METHODS AND RESULTS: In 29 separate studies, 20 903 white subjects were screened for >/=1 of these substitutions; each meta-analysis included only some of these individuals. In population-based studies, heterozygote frequencies ranged from 0.04% to 0.2%, 2% to 4%, 1% to 7%, and 17% to 22% for the respective substitutions. Postheparin plasma lipoprotein lipase activity decreased 53% (95% CI, 31% to 75%) (only 1 study), 30% (22% to 37%), and 22% (8% to 35%) and was unchanged at 4% (-10% to 19%), respectively. Plasma triglycerides increased 78% (95% CI, 64% to 92%), 20% (9% to 33%), and 31% (20% to 43%) and decreased 8% (4% to 11%), respectively. HDL cholesterol decreased 0. 25 mmol/L (0.18 to 0.32), 0.08 mmol/L (0.04 to 0.12), and 0.12 mmol/L (0.10 to 0.15) and increased 0.04 mmol/L (0.02 to 0.06), respectively. Odds ratios for ischemic heart disease were 4.9 (95% CI, 1.2 to 20) (only 1 study), 1.4 (0.8 to 2.4), 1.2 (0.9 to 1.5), and 0.8 (0.7 to 1.0), respectively. Subgroup analysis indicated that women with the Asn291Ser substitution may have an increased risk of ischemic heart disease. CONCLUSIONS: These meta-analyses suggest that compared with noncarriers, carriers of the Gly188Glu, Asp9Asn, and Asn291Ser substitutions have an atherogenic lipoprotein profile, whereas carriers of the Ser447Ter substitution have a protective lipoprotein profile. Accordingly, risk of ischemic heart disease in heterozygous carriers is increased for Gly188Glu carriers; at most, the increase is borderline for Asp9Asn and Asn291Ser carriers; and risk is possibly decreased for Ser447Ter carriers.

Apolipoprotein A-I↗

PubMed1980

A-IMilano apoprotein. Decreased high density lipoprotein cholesterol levels with significant lipoprotein modifications and without clinical atherosclerosis in an Italian family.

Significant hypertriglyceridemia with a very marked decrease of high density lipoproteins (HDL)-cholesterol levels (7-14 mg/dl) was detected in three members (father, son, and daughter) of an Italian family. The three affected individuals did not show any clinical signs of atherosclerosis, nor was the atherosclerotic disease significantly present in the family. Lipoprotein lipase and lecithin:cholesterol acyltransferase activites were normal or slightly reduced. Morphological and compositional studies of HDL in the subjects showed a significant enlargement of the lipoprotein particles (approximately 120 vs. approximately 94 A for control HDL) and a concomitant increase in the triglyceride content. Analytical isoelectric focusing of HDL apoproteins provided evidence for multiple isoproteins in the apoprotein(apo)-A-I range, with nine different bands being detected instead of the usual four bands observed in normal subjects. Two-dimensional immunoelectrophoresis against apo-A antiserum indicated a clear reduction of apo-A in the alpha electrophoretic region, with splitting of the protein "peak." The observation in otherwise clinically healthy subjects of hypertriglyceridemia, reduced HDL-cholesterol, and marked apoprotein abnormalities, without a significant incidence of atherosclerotic disease in the family suggests this is a new disease entity in the field of lipoprotein pathology, very probably related to an altered amino acid composition of the apo-A-I protein (see Weisgraber et al. 1980. J. Clin. Invest. 66: 901-907).

Adolescent↗

PubMed1992

Plasma lipoprotein metabolism in transgenic mice overexpressing apolipoprotein E. Accelerated clearance of lipoproteins containing apolipoprotein B.

We have reported that transgenic mice overexpressing rat apo E shows marked reduction of plasma cholesterol and triglyceride levels due to the disappearance of VLDL and LDL. In this study, we investigated the metabolism of plasma lipoproteins in transgenic mice. After intravenous injection, the rates of clearance of 125I-VLDL and 125I-LDL were 3.0- and 2.4-fold greater in transgenic mice than in controls, respectively. Furthermore, clearance of chylomicron remnants estimated by oral retinyl palmitate-loading test was markedly enhanced in transgenic mice. The hepatic expression of LDL receptors by immunoblot analysis was similar in both groups. These data suggest that elimination of lipoproteins containing apo B was due to enhanced clearance of these lipoproteins enriched with apo E through hepatic LDL receptors. When fed a high cholesterol diet, controls showed twofold elevation of plasma cholesterol levels with marked increases in VLDL and LDL cholesterol on gel filtration chromatography. In contrast, cholesterol-fed transgenic mice showed resistance against these increases. High cholesterol feeding decreased the activity of hepatic LDL receptors and had no effect on enhancement of chylomicron remnant clearance in transgenic mice. Thus, overexpression of apo E facilitates metabolism of lipoproteins containing apo B presumably primarily via the LDL receptor pathway and possibly through an interaction with the chylomicron remnant receptor.

Animals↗

PubMed1993

Heterozygous lipoprotein lipase deficiency due to a missense mutation as the cause of impaired triglyceride tolerance with multiple lipoprotein abnormalities.

In 16 members of two Austrian families affected by a missense mutation at codon 188 of the lipoprotein lipase (LPL) gene (8 heterozygous and 8 normal subjects), carrier status for the mutation as determined by DNA analysis was related to LPL activity in postheparin plasma, to the magnitude of postprandial lipemia, and to concentration, composition, and size of the major lipoprotein classes of postabsorptive plasma. Carriers exhibited clearly reduced LPL activity, normal fasting triglycerides, but pronounced postprandial lipemia. The carriers' impaired triglyceride tolerance, as evident in the postprandial state of challenge only, was associated with a fasting lipoprotein constellation characterized by (a) enrichment of HDL2 with triglycerides, (b) reduced HDL2-cholesterol, (c) enrichment of VLDL and intermediate density lipoprotein (IDL) with cholesteryl esters, (d) elevated IDL levels, and (e) small-sized LDL. Within any given individual, the degrees of expression of these characteristics were quantitatively and continuously related with each other as well as with the magnitude of lipemia and with LPL activity.

Adolescent↗

PubMed2001

Lipoprotein (a) binds and inactivates tissue factor pathway inhibitor: a novel link between lipoproteins and thrombosis.

Lipoprotein (a) [Lp(a)] has been associated with both anti-fibrinolytic and atherogenic effects. However, no direct link currently exists between this atherogenic lipoprotein and intravascular coagulation. The current study examined the binding and functional effects of Lp(a), its lipoprotein constituents, apoliprotein (a) [apo(a)] and low-density lipoprotein (LDL), and lysine-plasminogen (L-PLG), which shares significant homology with apo(a), on tissue factor pathway inhibitor (TFPI), a major regulator of tissue factor-mediated coagulation. Results indicate that Lp(a), apo(a), and PLG but not LDL bound recombinant TFPI (rTFPI) in vitro and that apo(a) bound to a region spanning the last 37 amino acid residues of the c-terminus of TFPI. The apparent binding affinity for TFPI was much higher for Lp(a) (KD approximately 150 nM) compared to PLG (KD approximately 800 nM) and nanomolar concentrations of apo(a) (500 nM) inhibited PLG binding to TFPI. Lp(a) also inhibited in a concentration-dependent manner rTFPI activity and endothelial cell surface TFPI activity in vitro, whereas PLG had no such effect. Moreover physiologic concentrations of PLG (2 microM) had no effect on the concentration-dependent inhibition of TFPI activity induced by Lp(a). In human atherosclerotic plaque, apo(a) and TFPI immunostaining were shown to coexist in smooth muscle cell-rich areas of the intima. These data suggest a novel mechanism whereby Lp(a) through its apo(a) moiety may promote thrombosis by binding and inactivating TFPI.

Animals↗