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PubMed1991

Dissociation of high density lipoprotein precursors from apolipoprotein B-containing lipoproteins in the presence of unesterified fatty acids and a source of apolipoprotein A-I.

Incubation of low (LDL), intermediate (IDL), or very low density lipoproteins (VLDL) with palmitic acid and either high density lipoproteins (HDL), delipidated HDL, or purified apolipoprotein (apo) A-I resulted in the formation of lipoprotein particles with discoidal structure and mean particle diameters ranging from 146 to 254 A by electron microscopy. Discs produced from IDL or LDL averaged 26% protein, 42% phospholipid, 5% cholesteryl esters, 24% free cholesterol, and 3% triglycerides; preparations derived from VLDL contained up to 21% triglycerides. ApoA-I was the predominant protein present, with smaller amounts of apoA-II. Crosslinking studies of discs derived from LDL or IDL indicated the presence of four apoA-I molecules per particle, while those derived from large VLDL varied more in size and contained as many as six apoA-I molecules per particle. Incubation of discs derived from IDL or LDL with purified lecithin:cholesterol acyltransferase (LCAT), albumin, and a source of free cholesterol produced core-containing particles with size and composition similar to HDL2b. VLDL-derived discs behaved similarly, although the HDL products were somewhat larger and more variable in size. When discs were incubated with plasma d greater than 1.21 g/ml fraction rather than LCAT, core-containing particles in the size range of normal HDL2a and HDL3a were also produced. A variety of other purified free fatty acids were shown to promote disc formation. In addition, some mono and polyunsaturated fatty acids facilitated the formation of smaller, spherical particles in the size range of HDL3c. Both discoidal and small spherical apoA-I-containing lipoproteins were generated when native VLDL was incubated with lipoprotein lipase in the presence of delipidated HDL. We conclude that lipolysis product-mediated dissociation of lipid-apoA-I complexes from VLDL, IDL, or LDL may be a mechanism for formation of HDL subclasses during lipolysis, and that the availability of different lipids may influence the type of HDL-precursors formed by this mechanism.

Animals↗
PubMed1985

Isolation, characterization, and uptake in human fibroblasts of an apo(a)-free lipoprotein obtained on reduction of lipoprotein(a).

Treatment of native human Lp(a) under nondenaturing conditions with dithiothreitol yielded both a lipoprotein particle and a lipid-free protein component that could be separated by either ultracentrifugation at d 1.063 g/ml or heparin-Sepharose chromatography. The protein component only showed antigenicity against anti-Lp(a) but not against anti-B. It was heterogeneous according to SDS polyacrylamide gel electrophoresis (PAGE) consisting of two bands, a major band with molecular weight similar to apoB and a minor band with slightly lower molecular weight. The lipoprotein particle was similar to LDL with regard to its electrophoretic mobility, lipid-protein composition, its apparent molecular weight according to gel-exclusion chromatography, and its apoprotein content; only apoB was found to be present by SDS-PAGE and immunochemical analysis. This lipoprotein also proved to be identical to LDL in its uptake by the receptor-mediated LDL-pathway in cultured human fibroblasts as shown by the similarity of the concentration-dependent binding, internalization, and degradation curves at 37 degrees C of the 125I-labeled lipoproteins. Normal Lp(a) was not taken up as readily as either its reduced lipoprotein component or LDL in the various steps of the receptor-mediated pathway. The maximal capacity for Lp(a) in the degradation assay was only 25% of that of LDL and it had a fourfold higher Km. It is therefore probable that the LDL-receptor-mediated pathway is not a major route for the clearance of Lp(a) in vivo. These studies suggest that Lp(a) is, in essence, an LDL-particle to which the protein (a) is attached through disulfide bonds to apoB.

Chromatography, Affinity↗
PubMed1985

Rapid preparative isolation of concentrated low density lipoproteins and of lipoprotein-deficient serum using vertical rotor gradient ultracentrifugation.

In order to study cellular metabolism of low density lipoproteins (LDL), ultracentrifugal methods have been used to isolate the lipoproteins. The use of vertical rotor ultracentrifugation very quickly produces small quantities of diluted lipoproteins per gradient, as well as small volumes of lipoprotein-deficient serum. We present modifications to this method in order to prepare routinely more concentrated LDL and a sufficient volume of lipoprotein-deficient serum in a relatively short time with minimal cost and handling.

Electrophoresis, Polyacrylamide Gel↗
PubMed1982

Alterations in plasma proteins and lipoproteins in acute myocardial infarction: effects on activation of lipoprotein lipase.

Plasma lipoprotein concentrations were followed in 21 men with acute myocardial infarction. HDL and LDL cholesterol concentrations showed similar time-courses with average maximal decreases of about 20%, 10-14 days after onset of symptoms. The decrease in HDL levels (measured as HDL cholesterol and apolipoprotein AI) was significantly correlated to the inflammatory response, as reflected by plasma orosomucoid concentrations, and to the extent of myocardial injury, as mirrored by serum activities of lactate dehydrogenase. In samples drawn 10 days after myocardial infarction we found marked changes in the ability of the patients' sera to enhance the activity of purified lipoprotein lipase. The maximal activating ability (at saturating serum concentrations) increased by about 30%; however, at suboptimal serum concentrations, the activating ability of the patients' sera declined (50% higher serum concentrations were required to reach half maximal reaction rate). The altered activation characteristics were correlated to the changes in HDL concentrations. By affecting the activity of lipoprotein lipase and thereby the rate of intravascular lipoprotein metabolism, this phenomenon may contribute to the lipoprotein alterations seen after myocardial infarction.

Adult↗
PubMed1993

Abnormal activation of lipoprotein lipase by non-equilibrating apoC-II: further evidence for the presence of non-equilibrating pools of apolipoproteins C-II and C-III in plasma lipoproteins.

Using artificial triglyceride emulsions, we have demonstrated the presence of non-equilibrating pools of apolipoproteins C-II and C-III in human plasma lipoproteins. As the concentrations of acceptor triglycerides were increased, a greater fraction of both apoC-II and apoC-III shifted away from the native plasma lipoproteins to the artificial lipid emulsions. All of the apoC-II and apoC-III in very low density and high density lipoproteins (VLDL and HDL), however, could not be removed from native plasma lipoproteins. The percent of total plasma apoC-II and apoC-III that could be recovered in the VLDL and HDL density fractions varied when plasma from different individuals was used. When plasma samples from normotriglyceridemic subjects were used, HDL was the primary donor of apoCs. The percent of total plasma apoCs associated with HDL decreased from 60% to 25% for apoC-II and from 65% to 15% for apoC-III. When plasma samples from hypertriglyceridemic subjects were incubated with artificial lipid emulsions, VLDL was the primary donor of apoCs. HDL from hypertriglyceridemic subjects only accounted for 5-10% of total fasting plasma apoCs and did not contribute significantly to the final apoC contents of the artificial triglyceride emulsions. To evaluate the significance of the depletion of exchangeable apoCs from plasma HDL, we also examined the ability of control and apoC-depleted HDL to serve as activator for bovine milk lipoprotein lipase (LPL) in vitro. When HDL depleted of exchangeable apoCs were used as the source of plasma apolipoproteins for the activation of LPL in vitro, only 5-10% of the maximal activity obtained with native HDL was demonstrated. In fact, in the presence of comparable concentrations of HDL apoC-II, activation of LPL was the least with HDL which lacked exchangeable apoCs. Our data thus indicated that the presence of exchangeable apoC-II on HDL is necessary for the activation of LPL in vitro. This finding is consistent with our data that suggest that HDL from hypertriglyceridemic subjects do not stimulate LPL as well as HDL from normolipidemic subjects.

Animals↗
PubMed2001

Mutant of LolA, a lipoprotein-specific molecular chaperone of Escherichia coli, defective in the transfer of lipoproteins to LolB.

The outer membrane-specific lipoproteins of Escherichia coli are released from the inner membrane as a water-soluble complex with LolA and then transferred to the outer membrane receptor, LolB. LolA thus plays a critical role in the sorting and outer membrane localization of lipoproteins. To dissect the LolA function, the highly conserved residues were subjected to random mutagenesis, followed by selection for a growth defect. LolA(R43L), one of mutants thus constructed, possessed Leu in place of Arg at position 43 and caused accumulation of the LolA(R43L)-lipoprotein complex in the periplasm. LolA(R43L) was as active as wild-type LolA as to the release of lipoproteins from spheroplasts. In marked contrast, the transfer of lipoproteins from LolA(R43L) to LolB was completely inhibited, indicating that Arg at position 43 of LolA is involved in the lipoprotein transfer reaction.

Amino Acid Sequence↗
PubMed2004

Diet and lipoprotein oxidation: analysis of oxidized triacylglycerols in pig lipoproteins.

Oxidized lipoproteins have a recognized role in atherogenesis, but molecular-level research on oxidized lipids in lipoproteins and the effect of diet on these molecules have been limited. In the present study, the effects of three sunflower seed oil diets differing in oxidation levels (PV in oils 1, 84, and 223 mequiv O2/kg) on lipoprotein lipid oxidation in growing pigs were investigated. The emphasis was on the investigation of oxidized TAG molecules found in chylomicrons and VLDL. A method based on RP-HPLC and electrospray ionization-MS was used for the analysis of oxidized TAG molecules. The baseline diene conjugation method was used for the estimation of in vivo levels of lipoprotein lipid oxidation. Several oxidized TAG structures were found in the samples. These products consisted of TAG molecules with a hydroxy, an epoxy, or a keto group attached to a FA, and of TAG molecules containing an aldehyde structure derived from a FA. The lipoprotein lipids and TAG were more oxidized in the pigs fed on the most oxidized oil compared with those fed on nonoxidized oil. Oxidation of dietary fat was reflected in the lipoprotein oxidation. New, detailed information on oxidized TAG molecules of chylomicrons and VLDL was obtained.

Animals↗
PubMed1996

Slow beta-migrating lipoprotein: an atherogenic subclass of low density lipoproteins.

OBJECTIVE: To clarify the possibility that midband Lp in LDL fractions might act as an atherogenic lipoprotein in their interaction with macrophages. DESIGN AND METHODS: Low density lipoproteins (LDL) isolated by zonal ultracentrifugation from midband lipoprotein-positive serum in type lib hyperlipidemics were subjected to polyacrylamide gel disc electrophoresis. RESULTS: A part of midband lipoprotein was observed between pre beta-and beta-band, in addition to the main beta-band. We named this midband lipoprotein "slow beta-migrating Lp (slow beta-Lp)." The larger LDL subfraction from midband-lipoprotein positive serum on Sepharose 2B column chromatography contained much slow beta-Lp, named slow beta-Lp-rich LDL. The smaller LDL subfraction contained a little slow beta-Lp, named slow beta-Lp-poor LDL. Slow beta-Lp-rich LDL had similar composition to the control LDL except for apolipoprotein E. The uptake of [3H]cholesteryl linoleate-labeled slow beta-Lp-rich LDL by J774 macrophages was higher than that of control LDL. The cholesterol ester content of J774 macrophages incubated with slow beta-Lp-rich LDL increased significantly compared with slow beta-Lp-poor LDL, beta-VLDL, and control LDL. CONCLUSION: These results suggest that slow beta-Lp in type llb might generate foam cells from macrophages in atherosclerotic lesions.

Animals↗
PubMed1996

Increased esterification of cholesterol and transfer of cholesteryl ester to apo B-containing lipoproteins in Type 2 diabetes: relationship to serum lipoproteins A-I and A-II.

This study examines the activity of two key enzymes of reverse cholesterol transport, cholesterol ester transfer protein (CETP) and lecithin:cholesterol acyl transferase (LCAT) in 21 patients with non-insulin dependent diabetes mellitus (NIDDM) and 21 control subjects. Serum CETP was assessed by measuring plasma-mediated cholesteryl ester transfer between pooled exogenous lipoprotein with endogenous LCAT inhibited--an estimate of CETP mass. CETP activity was determined as cholesteryl ester transfer in the presence of the patients' lipoproteins and LCAT (endogenous assay). LCAT activity was determined in the same assay. There was no significant difference in CETP mass between the diabetic and non-diabetic subjects and there was no correlation between CETP mass and LCAT activity. Using the endogenous lipoprotein assay, CETP was elevated in serum from diabetic patients compared to control subjects (10.05 +/- 1.89 vs. 5.50 +/- 0.53 nmol/ml/h P < 0.05). LCAT was also increased in the diabetic patients (53.63 +/- 4.70 vs. 41.22 +/- 3.40 nmol/ml/h P < 0.05). Serum free cholesterol from diabetic and control subjects correlated with CETP activity measured using endogenous lipoprotein assay (r = 0.77, P < 0.001 and r = 0.82, P < 0.001), and also with LCAT activity (r = 0.76, P < 0.01 and r = 0.79, P < 0.01). There was a negative correlation between CETP activity with the endogenous lipoprotein assay and serum high density lipoprotein (HDL) cholesterol in the diabetic patients (r = -0.38, P < 0.01), but not in control subjects. In a subgroup of 10 control subjects, there was a positive correlation between LCAT activity and apolipoprotein (apo) A-I (r = 0.49, P < 0.05) and apo A-II (r = 0.51, P < 0.05) and also between CETP activity (endogenous assay) and apo A-I (r = 0.87, P = 0.001) and apo A-II (r = 0.63, P < 0.05). No relationship was observed between CETP activity and apo A-I or apo A-II in the diabetic subjects. Thus, serum CETP mass was normal in Type 2 diabetes but CETP activity (endogenous assay) was increased and was related to free cholesterol levels and LCAT activity in both diabetic and non-diabetic subjects.

Adult↗
PubMed1983

Plasma lipoprotein retinoids after vitamin A feeding in normal man: minimal appearance of retinyl esters among low-density lipoproteins.

Retinyl esters have been thought to be carried solely by lipoproteins of intestinal origin (chylomicrons and their catabolic derivatives). Recent reports, however, have indicated that there may be significant transfer of retinyl esters from chylomicrons to low-density lipoproteins (LDL) in vitro, and that in other species, substantial amounts of retinyl esters may appear in LDL. Since in man lipoproteins of intestinal origin are not considered to contribute to a quantitatively significant extent to circulating LDL, we have examined this issue further. The distribution of retinol and retinyl esters within the plasma lipoproteins of eight normal human volunteers was measured following the ingestion of vitamin A along with a mixed meal. Retinyl esters appeared in the chylomicrons and very-low-density lipoproteins. Small amounts of retinyl esters were also detected in the intermediate- and low-density lipoprotein (LDL) classes. Estimates of the masses of retinyl esters, however, indicated that 5% or less of chylomicron retinyl esters appeared in the LDL. These observations are consistent with orderly chylomicron delipidation and provide further evidence that chylomicron-derived components do not contribute directly or to a quantitatively significant extent to circulating LDL.

Adult↗
PubMed1984

The relationship between very-low-density lipoprotein lipid and measures of carbohydrate metabolism in children with different lipoprotein profiles: Bogalusa Heart Study.

The relationship of VLDL lipid (cholesterol and triglycerides) levels to fasting and postglucose plasma glucose, plasma glucose, insulin, and free fatty acid (FFA) levels were examined in four subgroups of children (n = 311, ages 6 to 18 years) from a total biracial population whose earlier beta- or pre-beta-lipoprotein cholesterol levels (or both) were in the extreme quintiles or quartiles. High beta-lipoprotein cholesterol strata with or without elevated pre-beta-lipoprotein cholesterol showed significantly high levels of FFA and glucose response (mean, 30 and 60 minutes) to oral glucose load, whereas postglucose insulin responses were markedly higher in the high pre-beta-lipoprotein cholesterol strata. VLDL triglycerides related closely with fasting plasma glucose levels (r = 0.53 to 0.60, P less than 0.001) and to a lesser extent with postglucose plasma glucose response (r = 0.37 to 0.44, P less than 0.001) in all cases. For insulin and FFA, however, correlations were significant only in certain subgroups. Similar relationships were noted for VLDL cholesterol. Measurements relating to carbohydrate tolerance, age, and race accounted for 35% to 48% of the variability in VLDL lipid values. Surprisingly, fasting plasma glucose showed the highest partial regression coefficient for VLDL lipid in all subgroups except high pre-beta-lipoprotein cholesterol and low beta-lipoprotein cholesterol category, in which age was the major predictor variable. These results demonstrate that subtle abnormalities in the above-mentioned metabolic interrelationships are established early in life.

Adolescent↗
PubMed1996

Effects of gemfibrozil or simvastatin on apolipoprotein-B-containing lipoproteins, apolipoprotein-CIII and lipoprotein(a) in familial combined hyperlipidaemia.

BACKGROUND: Familial combined hyperlipidaemia (FCH), characterized by elevated very-low-density lipoprotein (VLDL) and/or low-density lipoprotein (LDL), is associated with an increased prevalence of premature cardiovascular disease. Therefore, lipid-lowering is frequently indicated. METHODS: We evaluated in a parallel, double-blind randomized fashion the effect of gemfibrozil (1200 mg/day) (n = 40) or simvastatin (20 mg/day) (n = 41) on lipids, apolipoprotein-B (apo-B)-containing lipoproteins, apo-CIII and lipoprotein(a) [Lp(a)], in 81 well-defined FCH patients. RESULTS: While both drugs lowered plasma cholesterol and triglyceride levels, gemfibrozil lowered plasma triglycerides more effectively by reduction of triglycerides in VLDL and LDL, whereas simvastatin was more effective in its reduction of total plasma cholesterol by exclusively decreasing LDL cholesterol. High-density lipoprotein (HDL) increased to an equal extent on both therapies. Total serum apo-B levels were reduced with both drugs; however, gemfibrozil decreased apo-B only in VLDL + IDL, whereas simvastatin decreased apo-B in both VLDL + IDL and LDL. In keeping with a more effective reduction of VLDL particles, a more pronounced reduction of apo-CIII also was observed after gemfibrozil, which correlated with the reduction in plasma triglycerides. Baseline concentrations of Lp(a) showed a wide range in both treatment groups. Median Lp(a) levels increased after simvastatin, but were not affected by gemfibrozil. CONCLUSION: Both therapies exhibited their specific effects, although none of the drugs alone completely normalized the lipid profiles of these patients with FCH. Therefore, the choice of treatment should be based on the most elevated lipoprotein fraction, and in some cases a combination of the two drugs may be indicated.

Adult↗
PubMed2005

Myeloperoxidase-mediated oxidation of high-density lipoproteins: fingerprints of newly recognized potential proatherogenic lipoproteins.

Substantial evidence supports the notion that oxidative processes participate in the pathogenesis of atherosclerotic heart disease. Major evidence for myeloperoxidase (MPO) as enzymatic catalyst for oxidative modification of lipoproteins in the artery wall has been suggested in numerous studies performed with low-density lipoprotein. In contrast to low-density lipoprotein, plasma levels of high-density lipoprotein (HDL)-cholesterol and apoAI, the major apolipoprotein of HDL, inversely correlate with the risk of developing coronary artery disease. These antiatherosclerotic effects are attributed mainly to HDL's capacity to transport excess cholesterol from arterial wall cells to the liver during 'reverse cholesterol transport'. There is now strong evidence that HDL is a selective in vivo target for MPO-catalyzed oxidation impairing the cardioprotective and antiinflammatory capacity of this antiatherogenic lipoprotein. MPO is enzymatically active in human lesion material and was found to be associated with HDL extracted from human atheroma. MPO-catalyzed oxidation products are highly enriched in circulating HDL from individuals with cardiovascular disease where MPO concentrations are also increased. The oxidative potential of MPO involves an array of intermediate-generated reactive oxygen and reactive nitrogen species and the ability of MPO to generate chlorinating oxidants-in particular hypochlorous acid/hypochlorite-under physiological conditions is a unique and defining activity for this enzyme. All these MPO-generated reactive products may affect structure and function of HDL as well as the activity of HDL-associated enzymes involved in conversion and remodeling of the lipoprotein particle, and represent clinically useful markers for atherosclerosis.

Animals↗
PubMed2006

Low-density lipoproteins generated during an oral fat load in mild hypertriglyceridemic and healthy subjects are smaller, denser, and have an increased low-density lipoprotein receptor binding affinity.

Triglyceride-rich lipoproteins generated during the postprandial phase are atherogenic. Large very low-density lipoproteins (LDLs) or chylomicrons (CMs) are not as atherogenic as their remnants (Rem). Small and dense LDLs are associated with cardiovascular disease. Low-density lipoprotein size is partly under genetic control and is considered as a relatively stable LDL feature. In this article, we present data on retinyl palmitate kinetics correlated with the modification of LDL features in terms of size, density, and in vitro receptor binding affinity after an oral fat load. Six nondiabetic, hypertriglyceridemic (HTG) patients and 6 healthy controls were examined. Low-density lipoprotein size was assessed by gradient gel electrophoresis, and LDL density by density gradient ultracentrifugation. Low-density lipoprotein binding affinity was tested by in vitro competition binding assay on normal human skin fibroblasts (HSFs) and hepatoma cells (HepG2). Kinetic parameters were estimated in CM and Rem fractions by compartmental modeling. Hypertriglyceridemic patients showed significantly higher triglyceride area and a slower CM fractional catabolic rate. Postprandial LDL density increased both in HTG patients and in the control group with a significant difference between groups at 6 hours. Fasting LDL size was lower in HTG patients vs controls but decreased similarly in the postprandial phase. Low-density lipoprotein size and density postprandial modifications were not correlated with any investigated parameter. Postprandial LDLs were internalized more efficiently by HSF than baseline LDL only in the HTG group. In conclusion, postprandial LDLs are smaller and denser compared with fasting LDLs after an oral fat load. Postprandial LDLs also slightly increased their affinity to the HSF cell receptors.

Adult↗
PubMed1996

The relation of plasma triglyceride, apolipoprotein B, and high-density lipoprotein cholesterol to postheparin lipoprotein lipase activity is dependent on apolipoprotien E polymorphism.

Postheparin plasma (PH)-lipoprotein lipase (LPL) activity has been reported to be a significant correlate of plasma triglyceride and high-density lipoprotein cholesterol (HDL-C) levels. However, some studies have failed to observe these associations. In this regard, apolipoprotein (apo) E polymorphism may play an important role, since the apo E2 isoform has unfavorable effects on the catabolism of triglyceride-rich lipoprotein particles. We have thus examined the relationships between PH-LPL activity and plasma lipoprotein-lipid levels within groups of men classified on the basis of apo E phenotypes, to verify whether apo E polymorphism could alter these associations. In men carrying the apo E2 isoform (n = 12), PH-LPL activity showed a strong negative correlation with plasma triglyceride (r = -.72, P < .01), very-low-density lipoprotein (VLDL) triglyceride ([VLDL-TG] r = -.83, P < .001), and VLDL cholesterol ([VLDL-C] r = -.57, P < .05) levels and a positive correlation with plasma HDL-C (r = .87, P < .001) and HDL2-C (r=.90, P < .001) concentrations. These correlations were also noted for plasma apo B levels (r = -.65, P < .05), VLDL-apo B concentrations (r= -.76, P < .01), and the HDL-C to cholesterol ratio (r = .85, P < .001). In contrast, none of these associations were found in men carrying the apo E4 isoform (n = 11). In men homozygous for the apo E3 isoform (n = 29), PH-LPL activity was only significantly correlated with plasma HDL2-C levels (r = .46, P < .01). Results of the present study indicate that PH-LPL activity is related to plasma triglyceride, VLDL-TG, VLDL-C, VLDL-apo B, apo B, and HDL-C levels and the HDL-C to cholesterol ratio in men carrying the apo E2 isoform, but not in men homozygous for the apo E3 isoform or among apo E4 carriers. Thus, apo E polymorphism appears to modulate the effect of variation in PH-LPL activity on the plasma lipoprotein profile.

Adult↗
PubMed1996

Adenoviral delivery of low-density lipoprotein receptors to hyperlipidemic rabbits: receptor expression modulates high-density lipoproteins.

Plasma concentrations of low-density lipoproteins (LDLs) and high-density lipoproteins (HDLs) are inversely related in several dyslipoproteinemias. To elucidate the interactions between these lipoproteins, we used a recombinant adenovirus (hLDLR-rAdV) to express human LDL receptors (hLDLRs) in LDL receptor-deficient rabbits. hLDLR-rAdV administration resulted in hepatocyte expression and a reduction of total, intermediate-density lipoprotein (IDL), and LDL cholesterol. In addition, we found that hLDLR-rAdV treatment induced (1) increased very-low-density lipoprotein (VLDL) cholesterol, (2) increased VLDL, IDL and LDL triglycerides, (3) decreased alpha- and pre-beta-migrating apolipoprotein E (apo E) and decreased pre-beta-migrating apo A-I at 2 to 4 days posttreatment, and (4) increased total plasma apo A-I and pre-beta-migrating apo A-I beginning 8 to 10 days posttreatment. Virtually all plasma apo A-I was present on alpha- and pre-beta-HDL. Pre-beta-HDL particles with size and electrophoretic properties consistent with nascent HDL demonstrated the greatest relative apo A-I enrichment following hLDLR-rAdV treatment. In summary, enhanced expression of hepatocyte LDLRs by hLDLR-rAdV treatment markedly altered apo A-I-containing lipoproteins and IDL and LDL. The use of recombinant viruses to express physiologically relevant genes in intact animals, analogous to transfection of cells in culture, provides a new strategy for the evaluation of effects of specific gene products on metabolic systems in vivo.

Adenoviridae↗
PubMed1997

Modulation of lipoprotein(a) atherogenicity by high density lipoprotein cholesterol levels in middle-aged men with symptomatic coronary artery disease and normal to moderately elevated serum cholesterol. Regression Growth Evaluation Statin Study (REGRESS) Study Group.

OBJECTIVES: This study sought to examine whether lipoprotein(a) levels predict coronary artery lumen changes in patients with symptomatic coronary artery disease (CAD) and normal to moderate hypercholesterolemia. BACKGROUND: Recent conflicting reports have confirmed or refuted the association of lipoprotein(a) with clinical events or angiographically verified disease progression. METHODS: The association between serum lipoprotein(a) and changes in coronary artery lumen was studied in 704 men entered into the Regression Growth Evaluation Statin Study (REGRESS), a double-blind, placebo-controlled, quantitative angiographic study that assessed the effect of 2 years of pravastatin treatment. The primary end points were changes in average mean segment diameter (MSD) and average minimal obstruction diameter (MOD). Pravastatin- and placebo-treated patients were classified as having progressing, regressing or stable CAD, and median lipoprotein(a) concentrations were compared. Bivariate and multivariate regression analyses were performed in the overall patient group and in high risk subgroups. RESULTS: Pravastatin treatment did not affect serum apolipoprotein(a) levels. Median in-trial (sampled at 24 months) apolipoprotein(a) levels for regressing, stable and progressing CAD were, respectively, 130, 162 and 251 U/liter in placebo-treated patients and 143, 224 and 306 U/liter in pravastatin-treated patients. Predictors of MSD and MOD changes were baseline MSD and MOD, in-trial apolipoprotein(a), in-trial high density lipoprotein (HDL) cholesterol and baseline use of long-acting nitrates. The multivariate models predicted 14% of MSD changes and 12% of MOD changes; apolipoprotein(a) predicted only 2.6% and 4.8%, respectively. However, in patients with in-trial HDL cholesterol levels <0.7 mmol/liter, apolipoprotein(a) predicted up to 37% of the arteriographic changes. CONCLUSIONS: Serum lipoprotein(a) levels predict coronary artery lumen changes in normal to moderately hypercholesterolemic white men with CAD; its atherogenicity is marked in the presence of concomitant hypoalphalipoproteinemia.

Anticholesteremic Agents↗
PubMed1993

Oxidation of low-density lipoprotein with hypochlorite causes transformation of the lipoprotein into a high-uptake form for macrophages.

Oxidation of low-density lipoprotein (LDL) lipid is thought to represent the initial step in a series of oxidative modification reactions that ultimately transform this lipoprotein into an atherogenic high-uptake form that can cause lipid accumulation in cells. We have studied the effects of hypochlorite, a powerful oxidant released by activated monocytes and neutrophils, on isolated LDL. Exposure of LDL to reagent hypochlorite (NaOCl) at 4 degrees C resulted in immediate and preferential oxidation of amino acid residues of apoprotein B-100, the single protein associated with LDL. Neither lipoprotein lipid nor LDL-associated antioxidants, except ubiquinol-10, represented major targets for this oxidant. Even when high concentrations of NaOCl were used, only low levels of lipid hydroperoxides could be detected with the highly sensitive h.p.l.c. post-column chemiluminescence detection method. Lysine residues of apoprotein B-100 quantitatively represented the major target, scavenging some 68% of the NaOCl added, with tryptophan and cysteine together accounting for an additional 10% of the oxidant. Concomitant with the loss of LDL's amino groups, chloramines were formed and the anionic surface charge of the lipoprotein particle increased, indicated by a 3-4-fold increase in electrophoretic mobility above that of native LDL on agarose gels. While both these changes could be initially reversed by physiological reductants such as ascorbic acid and methionine, incubation of the NaOCl-modified LDL at 37 degrees C resulted in increasing resistance of the modified lysine residues against reductive reversal. Exposure of mouse peritoneal macrophages to NaOCl-oxidized LDL resulted in increased intracellular concentrations of cholesterol and cholesteryl esters. These findings suggest that lipid-soluble antioxidants associated with LDL do not efficiently protect the lipoprotein against oxidative damage mediated by hypochlorite, and that extensive lipid oxidation is not a necessary requirement for oxidative LDL modification that leads to a high-uptake form of the lipoprotein.

Acetylation↗