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PubMed1990

Lipoprotein(a) binding to other apolipoprotein B containing lipoproteins.

A method combining ligand dot blotting and digital imaging was used to determine the apparent dissociation constant (KD) for the binding of lipoprotein(a) to low-density lipoproteins (Lp(a)-LDL2). By use of this approach, the KD for the Lp(a)-LDL2 complex was shown to be in the nanomolar range [(1.05 +/- 0.21) x 10(-8) M, n = 4]. The Lp(a)-LDL2 interaction was both hydrophobic and ionic; however, hydrophobic forces predominated because the interaction was demonstrable at high salt concentration (greater than 2 M NaCl), while no complex was detectable at low salt concentration (less than 0.08 M NaCl). Consistent with the hydrophobic nature of this interaction, the Lp(a)-LDL2 complex was stable over a wide pH range (4-10). Plasminogen did not compete with Lp(a) binding to LDL2 even at a 2.2 X 10(3) molar excess of plasminogen over the LDL2 concentration. The only component identified in plasma and serum that inhibited the binding of LDL2 to Lp(a) was apolipoprotein B containing lipoproteins (apoB-Lp). These studies indicate that the Lp(a)-LDL2 complex could exist in plasma. In fact, up to 72% of purified Lp(a) added to an Lp(a)-negative hypertriglyceridemic plasma floated with apoB-Lp (d less than 1.063 g/mL) following ultracentrifugation, whereas only 9% of the purified Lp(a) added to the apoB-Lp-free 1.12 g/mL infranate floated at d less than 1.063 g/mL. The formation of a complex of Lp(a) with apoB-Lp could increase the amount of cholesterol ester bound per cellular receptor, e.g., LDL receptor, and thus potentially accelerate cholesterol removal from the vascular compartment.

Animals↗

PubMed1992

A high-density-lipoprotein receptor appears to mediate the transfer of essential fatty acids from high-density lipoprotein to lymphocytes.

It has been shown previously that a specific high-density lipoprotein (HDL) receptor exists on human lymphocytes that recognizes apoprotein (apo) A1 as its ligand, and may be responsible for utilization of HDL lipids to respond optimally to mitogenic stimulation when cultured in serum-free medium supplemented with HDL. To clarify further the relationship between various HDL lipids used by lymphocytes and HDL receptor activity, the lipid composition of the cells and the regulation of HDL and low-density lipoprotein (LDL) receptors on freshly isolated lymphocytes and mitogen-activated T-blasts after treatment with lipoproteins, liposomes or fatty acids were investigated. Our data show that the linear increase in cell proliferation correlates with the presence of HDL in fatty-acid-free culture medium in the concentration range of HDL receptor saturation. Decreased binding/uptake of dioctadecylindocarbocyanine (DiI)-fluorescence-labelled HDL by freshly isolated lymphocytes was observed in the presence of unlabelled HDL in 4-day culture, whereas T-blast binding/uptake was down-regulated by preincubation not only with HDL but also with LDL. T-blasts pretreated with HDL showed increased cellular contents of phosphatidylcholine, oleic acid (C18:1,n-9) and linoleic acid (C18:2,n-6), which are essential for optimal proliferation of mitogen-stimulated lymphocytes. Furthermore, DiI-HDL binding on lymphocytes was down-regulated by up to 20% (resting T cells) and 50% (T-blasts) when cultured in the presence of apoA1-phosphatidylcholine liposomes (T-blasts only), oleic acid or linoleic acid, but not by stearic acid (C18:0). The results indicate that HDL provide lymphocytes with essential fatty acids, which in turn regulate HDL receptor activity.

Adult↗

PubMed1997

Segments in the C-terminal folding domain of lipoprotein lipase important for binding to the low density lipoprotein receptor-related protein and to heparan sulfate proteoglycans.

Lipoprotein lipase (LpL) can mediate cellular uptake of chylomicron and VLDL remnants via binding to heparan sulfate proteoglycans (HSPG) and the endocytic alpha2-macroglobulin receptor/low density lipoprotein receptor-related protein (alpha2MR/LRP). Whereas it is established that the C-terminal folding domain binds to alpha2MR/LRP, it remains uncertain whether it binds to heparin and to HSPG. To identify segments important for binding to alpha2MR/LRP and to clarify possible binding to heparin, we produced constructs of the human C-terminal folding domain, LpL-(313-448), and of the fragment LpL-(347-448) in Escherichia coli. In addition to binding to alpha2MR/LRP, LpL-(313-448) displayed binding to heparin with an affinity similar to that of the LpL monomer, whereas it bound poorly to lipoprotein particles. Moreover, LpL-(313-448) displayed heparin sensitive binding to normal, but not to HSPG deficient Chinese hamster ovary cells. LpL-(313-448) and LpL-(347-448) showed similar affinities for binding to both purified alpha2MR/LRP and to heparin. Deletion of LpL residues 380-384 abolished the binding to LRP, whereas binding to heparin was unperturbed. The binding to both heparin and alpha2MR/LRP was essentially abolished following deletion of residues 404-430, and pretreatment of CHO cells with the peptide comprising aa 402-423 inhibited the binding of LpL-(313-448). We conclude that the C-terminal folding domain of human LpL has a site for binding to heparin and to HSPG, presumably involving amino acids within residues 404-430. Two segments of the domain are necessary for efficient binding to alpha2MR/LRP, one comprising residues 380-384 and another overlapping the segment important for binding to heparin.

Animals↗

PubMed1997

Lipoprotein lipase (EC 3.1.1.34) targeting of lipoproteins to receptors.

Summarizing all available data on the role of lipases in targeting lipoproteins to their receptors, we propose the following model: TRL after hydrolysis by LPL have apo E exposed on their surface and might contain one or more molecules of LPL. Both 'apolipoproteins' direct the particles to the cell surface by high-affinity binding to cellular proteoglycans. HL, bound to the surface of hepatocytes can further hydrolyse the particles and together with apo E and LPL mediate the binding to cellular receptors. The most important receptors recognizing these remnants are LRP and VLDLR. The LRP seems to be mainly responsible for the hepatic uptake of remnant lipoproteins, while the VLDLR, mainly located in adipose tissue and muscle, might target the lipoproteins to these tissues for fatty acid delivery.

Humans↗

PubMed1982

Relationships between the metabolism of high-density and very-low-density lipoproteins in man: studies of apolipoprotein kinetics and adipose tissue lipoprotein lipase activity.

In order to gain further insight into the relationship between high-density lipoprotein (HDL) metabolism and plasma triglyceride transport, measurements were made of HDL cholesterol concentration, apoprotein (apo) AI and AII metabolism, very-low-density-lipoprotein (VLDL) apo B metabolism, and heparin-elutable adipose tissue lipoprotein lipase (LPL) activity in seventeen subjects with a wide range of plasma triglyceride concentrations (0.8-25 mmol/l). The fractional catabolic rate (FCR) of VLDL apo B was directly related to LPL activity (r = +0.80), providing evidence that the activity of the enzyme in adipose tissue is a determinant of the rate of lipolysis of VLDL in man. HDL cholesterol concentration was a positive function of both VLDL apo B FCR (r = +0.74) and LPL activity, a finding consistent with previous evidence for the origin of a proportion of HDL cholesterol from 'surface remnants' liberated during VLDL catabolism. THe FCRs of both apo AI and apo AII were inversely related to VLDL apo B FCR (AI, r = -0.52; AII, r = -0.69) and to LPL activity. The synthetic rate of ap AII, but not that of apo AI, was positively correlated with VLDL apo B synthesis (r = +0.7 1). Thus, the metabolism of the major proteins of HDl in man appears to be closely associated with VLDL metabolism.

Adipose Tissue↗

PubMed1984

Lipoproteins from the blood and egg yolk of the hen. The transfer of very-low-density lipoprotein to egg yolk and possible changes to apoprotein B.

As part of a study of the transfer of proteins and lipids from avian blood to egg yolk, some properties of lipoproteins from the blood of laying hens were compared with those of the low-density lipoprotein (YLP) from egg yolk of the same hens. Although it is known from previous work that particles of the very-low-density lipoprotein (VLDL) of blood are the most likely precursors of YLP, their apoprotein patterns are different, according to electrophoresis and chromatography, with only one protein in common. YLP has the more complicated pattern which does not, however, include apoprotein B (ApoB) the main apoprotein of VLDL. It is suggested that during the transfer of VLDL to yolk, ApoB is cleaved to give smaller yolk apoproteins, especially apovitellenins IV and VI. Some evidence for this suggestion from the similarity of protein digests is presented.

Amino Acid Sequence↗

PubMed1997

Uptake by J774 macrophages of very-low-density lipoproteins isolated from apoE-deficient mice is mediated by a distinct receptor and stimulated by lipoprotein lipase.

Apolipoprotein (apo) E-deficient mice display marked accumulation in the plasma of VLDL deficient in both apoE and apoB100 but containing apoB48, apoA-I, apoCs, and apoA-IV. Since apoE-deficient mice develop severe atherosclerotic lesions with lipid-laden macrophages, we reasoned that the uptake of lipoproteins by intimal macrophages can take place in the absence of both apoE and apoB100. To get more insight into the mechanism of foam cell formation in apoE-deficient mice, we measured the interaction of VLDL from apoE-deficient mice (apoEnull VLDL) with the murine macrophage cell line J774. Scatchard analysis revealed that apoEnull VLDL is bound to J774 cells with a Kd value comparable to that of control VLDL (8.1 versus 4.7 micrograms/mL) and with a Bmax value about half that of control VLDL (40 versus 70 ng/mg cell protein, respectively). ApoEnull VLDL is also taken up and degraded by J774 macrophages via a high-affinity process less efficiently than control mouse VLDL (6-fold and 50-fold less efficiently, respectively). In line with this observation, incubation of J774 cells with 50 micrograms/mL apoEnull VLDL for 24 hours resulted in an increase in intracellular cholesteryl ester (CE) content, although 5-fold less pronounced than after incubation with 50 micrograms/mL control mouse VLDL. Under the conditions applied, simultaneous addition of 5 micrograms/mL lipoprotein lipase (LPL) stimulated the cellular uptake and degradation of apoEnull VLDL about 10-fold and resulted in a 5-fold stimulation of the intracellular CE accumulation, from 9 +/- 2 to 46 +/- 5 micrograms CE per milligram cell protein. In contrast to control mouse VLDL, apoEnull VLDL could not compete with 125I-labeled LDL for binding to the LDL receptor of J774 cells. Furthermore, neither LDL nor acetylated LDL could compete with 125I-labeled apoEnull VLDL for binding to these cells, whereas control mouse VLDL, VLDL from a hypertriglyceridemic patient, and apoEnull VLDL itself were efficient competitors. Thus, VLDL from apoE-deficient mice is taken up by J774 macrophages through recognition by a distinct receptor, which could be the triglyceride-rich lipoprotein receptor. We conclude that in apoE-deficient mice, foam cell formation occurs via a receptor-mediated uptake of apoEnull VLDL, which can be stimulated by the presence of LPL.

Animals↗

PubMedDate not supplied

Neonatal umbilical cord blood lipoproteins. Isolation and characterization of intermediate density and low density lipoproteins.

Intermediate density lipoproteins (IDL) (d = 1.006 to 1.019 g/ml) and low density lipoproteins (LDL) (d = 1.019 to 1.063 g/ml) were isolated from human umbilical cord blood plasma by sequential ultracentrifugation. The concentration, chemical and apolipoprotein composition, size and size distribution of the neonatal IDL and LDL for both sexes were determined. The IDL and LDL from the neonates showed no sex-related differences in composition or concentration. The IDL and LDL were lower in concentration and differed in composition of concentration. The IDL and LDL were lower in concentration and differed in composition with regard to each other and with regard to the comparable adult fractions. The apolipoprotein (apo) composition showed only the high molecular weight form of apo B present in the IDL, while the LDL showed the presence of two lower molecular weight forms of apo B in addition to the high molecular weight form, along with appreciable amounts of apo E and apo A-l. The size distribution of the neonatal IDL and LDL showed a constant pattern, with peaks at approximately 300 A for IDL and 257 and 244 A for neonatal LDL. The alterations in composition, size and size distribution, as well as the lower concentrations present in neonate, point to differences between the neonate and the adult in the metabolism of lipoproteins with a density of 1.006 to 1.063 g/ml.

Adult↗

PubMed1979

Effect of moderate physical exercise on serum lipoproteins. A controlled clinical trial with special reference to serum high-density lipoproteins.

A controlled trial is reported on the effects of mild-to-moderate physical activity on serum lipoproteins. After two baseline examinations 100 asymptomatic middle-aged men were randomly assigned to exercise and control groups. The exercise group participated in a 4-month exercise program that consisted of 3-4 weekly sessions. The control group was advised to maintain their previous exercise habits. The success of the program was corroborated by the increase in VO2 in the training group, but not in the control group. Serum triglycerides decreased from 1.54 +/- 0.10 to 1.27 +/- 0.08 mmol/1 (p less than 0.001) and high-density lipoprotein (HDL) cholesterol increased from 1.27 +/- 0.04 to 1.41 +/- 0.04 mmol/1 (p less than 0.01) in the exercise group during the trial. No change was seen in the control group. As the concentration of apolipoprotein AI stayed constant in both groups, the ratio HDL cholesterol/apolipoprotein AI increased only in the exercise group. The level of low-density lipoprotein (LDL) cholesterol and apolipoprotein AII decreased in both groups during the trial. The alterations in serum triglycerides and HDL cholesterol in the exercise group were not dependent on weight reduction; similar changes were also seen in subjects with constant body weight during the intervention.

Adult↗

PubMed1997

Lipoprotein lipase increases lipoprotein binding to the artery wall and increases endothelial layer permeability by formation of lipolysis products.

Mechanisms responsible for the accumulation of low-density lipoprotein (LDL) were investigated in a new model, the perfused hamster aorta. To do this, we developed a method to study LDL flux in real time in individually perfused arteries; each artery served as its own control. Using quantitative fluorescence microscopy, the rates of LDL accumulation and efflux were separately determined. Perfusion of arteries with buffer plus lipoprotein lipase (LpL) increased LDL accumulation 5-fold (0.1 +/- 0.03 mV/min [control] versus 0.5 +/- 0.05 mV/min [LpL]) by increasing LDL retention in the artery wall. This effect was blocked by heparin and monoclonal antibodies directed against the amino-terminal region of apolipoprotein B (apo B). This suggests that specific regions of apo B are involved in LDL accumulation within arteries. Also, the effect of hydrolysis of triglyceride-rich lipoproteins on endothelial barrier function was studied. We compared endothelial layer permeability using a water-soluble reference molecule, fluorescently labeled dextran. When LpL was added to hypertriglyceridemic plasma, dextran accumulation within the artery wall increased > 4-fold (0.024 +/- 0.01 mV/min [control] versus 0.098 +/- 0.05 mV/min [LpL]). Under the same conditions, LpL increased LDL accumulation approximately 3-fold (0.016 +/- 0.003 mV/min [control] versus 0.047 +/- 0.013 mV/min [LpL]). Rapid efflux of LDL from the artery wall indicated that increased endothelial layer permeability was the primary mechanism during periods of increased lipolysis. Our data demonstrate two LpL-mediated effects that may increase the amount of LDL in the artery wall. These findings may pertain to the observed relationship between increased postprandial lipemia and atherosclerosis.

Animals↗

PubMed1998

Increased expression of apolipoprotein E in transgenic rabbits results in reduced levels of very low density lipoproteins and an accumulation of low density lipoproteins in plasma.

Transgenic rabbits expressing human apo E3 were generated to investigate mechanisms by which apo E modulates plasma lipoprotein metabolism. Compared with nontransgenic littermates expressing approximately 3 mg/dl of endogenous rabbit apo E, male transgenic rabbits expressing approximately 13 mg/dl of human apo E had a 35% decrease in total plasma triglycerides that was due to a reduction in VLDL levels and an absence of large VLDL. With its greater content of apo E, transgenic VLDL had an increased binding affinity for the LDL receptor in vitro, and injected chylomicrons were cleared more rapidly by the liver in transgenic rabbits. In contrast to triglyceride changes, transgenic rabbits had a 70% increase in plasma cholesterol levels due to an accumulation of LDL and apo E-rich HDL. Transgenic and control LDL had the same binding affinity for the LDL receptor. Both transgenic and control rabbits had similar LDL receptor levels, but intravenously injected human LDL were cleared more slowly in transgenic rabbits than in controls. Changes in lipoprotein lipolysis did not contribute to the accumulation of LDL or the reduction in VLDL levels. These observations suggest that the increased content of apo E3 on triglyceride-rich remnant lipoproteins in transgenic rabbits confers a greater affinity for cell surface receptors, thereby increasing remnant clearance from plasma. The apo E-rich large remnants appear to compete more effectively than LDL for receptor-mediated binding and clearance, resulting in delayed clearance and the accumulation of LDL in plasma.

Animals↗

PubMed1992

Conversion of human low density lipoprotein into a very low density lipoprotein-like particle in vitro.

The lipid substrate specificity of Manduca sexta lipid transfer particle (LTP) was examined in in vitro lipid transfer assays employing high density lipophorin and human low density lipoprotein (LDL) as donor/acceptor substrates. Unesterified cholesterol was found to exchange spontaneously between these substrate lipoproteins, and the extent of transfer/exchange was not affected by LTP. By contrast, transfer of labeled phosphatidylcholine and cholesteryl ester was dependent on LTP in a concentration-dependent manner. Facilitated phosphatidylcholine transfer occurred at a faster rate than facilitated cholesteryl ester transfer; this observation suggests that either LTP may have an inherent preference for polar lipids or the accessibility of specific lipids in the donor substrate particle influences their rate of transfer. The capacity of LDL to accept exogenous lipid from lipophorin was investigated by increasing the high density lipophorin:LDL ratio in transfer assays. At a 3:1 (protein) ratio in the presence of LTP, LDL became turbid (and aggregated LDL were observed by electron microscopy) indicating LDL has a finite capacity to accept exogenous lipid while maintaining an overall stable structure. When either isolated human non B very low density lipoprotein (VLDL) apoproteins or insect apolipophorin III (apoLp-III) were included in transfer experiments, the sample did not become turbid although lipid transfer proceeded to the same extent as in the absence of added apolipoprotein. The reduction in sample turbidity caused by exogenous apolipoprotein occurred in a concentration-dependent manner, suggesting that these proteins associate with the surface of LDL and stabilize the increment of lipid/water interface created by LTP-mediated net lipid transfer. The association of apolipoprotein with the surface of modified LDL was confirmed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis analysis, and scanning densitometry revealed that apoLp-III bound to the surface of LDL in a 1:14 apoB:apoLp-III molar ratio. Electron microscopy showed that apoLp-III-stabilized modified LDL particles have a larger diameter (29.2 +/- 2.6 nm) than that of control LDL (22.7 +/- 1.9 nm), consistent with the observed changes in particle density, lipid, and apolipoprotein content. Thus LTP-catalyzed vectorial lipid transfer can be used to introduce significant modifications into isolated LDL particles and provides a novel mechanism whereby VLDL-LDL interrelationships can be studied.

Animals↗

PubMed1991

Influence of dietary lipids on hepatic mRNA levels of proteins regulating plasma lipoproteins in baboons with high and low levels of large high density lipoproteins.

Selective breeding of baboons has produced families with increased plasma levels of large high density lipoproteins (HDL1) and very low (VLDL) and low (LDL) density lipoproteins when the animals consume a diet enriched in cholesterol and saturated fat. High HDL1 baboons have a slower cholesteryl ester transfer, which may account for the accumulation of HDL1, but not of VLDL and LDL. To investigate the mechanism of accumulation of VLDL + LDL in plasma of the high HDL1 phenotype, we selected eight half-sib pairs of baboons, one member of each pair with high HDL1, the other member with little or no HDL1 on the same high cholesterol, saturated fat diet. Baboons were fed a chow diet and four experimental diets consisting of high and low cholesterol with corn oil, and high and low cholesterol with lard, each for 6 weeks, in a crossover design. Plasma lipids and lipoproteins and hepatic mRNA levels were measured on each diet. HDL1 phenotype, type of dietary fat, and dietary cholesterol affected plasma cholesterol and apolipoprotein (apo) B concentrations, whereas dietary fat alone affected plasma triglyceride and apoA-I concentrations. HDL1 phenotype and dietary cholesterol alone did not influence hepatic mRNA levels, whereas dietary lard, compared to corn oil, significantly increased hepatic apoE mRNA levels and decreased hepatic LDL receptor and HMG-CoA synthase mRNA levels. Hepatic apoA-I message was associated with cholesterol concentration in HDL fractions as well as with apoA-I concentrations in the plasma or HDL. However, hepatic apoB message level was not associated with plasma or LDL apoB levels. Total plasma cholesterol, including HDL, was negatively associated with hepatic LDL receptor and HMG-CoA synthase mRNA levels. However, compared with low HDL1 baboons, high HDL1 baboons had higher concentrations of LDL and HDL cholesterol at the same hepatic mRNA levels. These studies suggest that neither overproduction of apoB from the liver nor decreased hepatic LDL receptor levels cause the accumulation of VLDL and LDL in the plasma of high HDL1 baboons. These studies also show that, in spite of high levels of VLDL + LDL and HDL1, the high HDL1 baboons had higher levels of mRNA for LDL receptor and HMG-CoA synthase. This paradoxical relationship needs further study to understand the pathophysiology of VLDL and LDL accumulation in the plasma of animals with the high HDL1 phenotype.

Animals↗

PubMed1984

Defective hepatic lipoprotein receptor binding of beta-very low density lipoproteins from type III hyperlipoproteinemic patients. Importance of apolipoprotein E.

Apolipoprotein (apo-) E2 and beta-migrating very low density lipoproteins (beta-VLDL) (which were isolated from type III hyperlipoproteinemic subjects) both demonstrated defective binding to apo-E and apo-B,E receptors on dog liver membranes and to apo-B,E low density lipoproteins (LDL) receptors on fibroblasts. The defective binding activity of the apo-E2 and beta-VLDL varied from very poor to nearly normal. The ability of the beta-VLDL to interact with hepatic apo-E receptors was enhanced by the addition of normal apo-E3 to the beta-VLDL. Furthermore, cysteamine treatment of the apo-E2 in beta-VLDL enhanced binding of the beta-VLDL to both apo-E and apo-B,E receptors. The importance of apo-E in mediating the receptor binding of beta-VLDL to these receptors was confirmed by using monoclonal antibodies. The residual binding activity of beta-VLDL to apo-E and apo-B,E receptors was inhibited by greater than 90% with anti-apo-E, while the addition of anti-apo-B had little effect. The apo-B in the beta-VLDL was capable of binding to apo-B,E receptors after the hydrolysis of the beta-VLDL triglycerides with milk lipoprotein lipase. Lipase treatment yielded, two subfractions of beta-VLDL. One fraction (d = 1.02 to 1.03 g/ml) was enriched with apo-B100; the other fraction (d less than 1.006 g/ml) was enriched with apo-B48 and apo-E2. Significantly increased amounts of the apo-B100-enriched fraction bound to apo-B,E receptors. Inhibition of this binding caused by the addition of anti-apo-B indicated that the binding activity of this subfraction was mediated by apo-B100. The apo-B48-enriched fraction did not show a significant increase in receptor binding, suggesting that apo-B48 does not bind to these receptors. In a control experiment, it was shown that triglyceride-rich VLDL, which contain normal apo-E3 and apo-B100, bind significantly to both liver apo-E receptors and fibroblast apo-B,E receptors. This binding activity was inhibited by greater than 90% with anti-apo-E. Lipase hydrolysis of the VLDL did not further enhance their receptor-binding activity. These results demonstrate that apo-E, and not apo-B, is the major determinant mediating the receptor-binding activity of cholesterol-rich beta-VLDL and triglyceride-rich VLDL.

Animals↗

PubMed1983

The role of lipoprotein lipase in the metabolism of triglyceride-rich lipoproteins by macrophages.

We have previously shown that cultured macrophages secrete lipoprotein lipase (LPL) into the culture medium. The purpose of these experiments was to determine the role of LPL in the uptake of very low density lipoproteins (VLDL). Both J774 cells and mouse peritoneal macrophages took up and degraded normotriglyceridemic VLDL in a saturable manner. Uptake of VLDL was effectively competed for by rabbit beta-VLDL, human VLDL, but not by native LDL or acetyl LDL. LPL activity accelerated saturable uptake of VLDL but was not a prerequisite for it. This was most clearly seen in experiments with apo-C-II-deficient VLDL. Although no hydrolysis of VLDL triglyceride occurred, saturable uptake and degradation of the C-II-deficient lipoprotein occurred. However, addition of apo-C-II enhanced saturable uptake. Normal VLDL also promoted cellular accumulation of both triglycerides and cholesteryl esters. Accumulation of triglyceride occurred by uptake of intact VLDL particles, by uptake of a triglyceride-depleted particle produced by the action of LPL, and by the direct uptake of free fatty acids generated by the activity of LPL. In turn, the latter process was influenced by the amount of albumin in the medium capable of being an acceptor for free fatty acids. Finally, we have shown that when albumin is present in the medium, the macrophage is capable of mobilizing most of its stored triglyceride over 24 h, even as its cholesteryl ester content remains constant. These studies may be relevant to the ability of VLDL to promote macrophage accumulation of cholesteryl ester, even as triglyceride accumulation is minimized.

Animals↗

PubMed1989

The effect of clomipramine treatment on plasma lipoproteins and high density lipoprotein subfractions in healthy subjects.

The effect of clomipramine on plasma lipoproteins, including high density lipoprotein (HDL) subfractions in five healthy males was investigated. The concentrations of total plasma cholesterol and low density lipoprotein cholesterol decreased slightly while that of total HDL-cholesterol showed a small increase, giving a decrease (p less than 0.05) in the ratio of total plasma cholesterol to HDL-cholesterol. The level of HDL2-cholesterol increased (p less than 0.01) with clomipramine treatment while there was no significant change in the concentration of HDL3-cholesterol. Gradient gel electrophoresis showed that administration of the drug was associated with an increase in the relative concentration of HDL2a as well as of HDL2b and a decrease in that of HDL3b/3c. The plasma concentration of apolipoprotein (Apo) A-I showed a small but insignificant increase. These changes in lipoprotein profile are characteristic of those associated with a decrease in coronary risk.

Adult↗

PubMed1998

Influence of risk factors on peripheral and cerebrovascular disease in men with coronary artery disease, low high-density lipoprotein cholesterol levels, and desirable low-density lipoprotein cholesterol levels. HIT Investigators. Department of Veterans Affairs HDL Intervention Trial.

BACKGROUND: The Veterans Administration-HDL Intervention Trial is an ongoing, 20-center, randomized, double-blind, placebo-controlled study aiming to assess the effect of gemfibrozil-improved low high-density lipoprotein cholesterol levels on cardiovascular morbidity and mortality rates. METHODS AND RESULTS: Eligible patients were men with low high-density lipoprotein cholesterol levels and demonstrable coronary heart disease. A total of 2531 patients (average age 63.5 years) were randomly assigned in this study, with a mean high-density lipoprotein cholesterol level of 0.83 mmol/L (32 mg/dL) and low-density lipoprotein cholesterol level of 2.87 mmol/L (111 mg/dL). Baseline data provided the opportunity to assess the interaction of several coronary heart disease risk factors and comorbid vascular diseases. Of these patients, 206 had diabetes mellitus (DM) alone, 1021 had hypertension (HTN) alone, 421 had both DM and HTN, and 883 had neither ("others"). Considering the influence of these risk factors on comorbidities independent of smoking status, patients with DM alone had a 2-fold increase in the prevalence of peripheral vascular disease and a 1.5-fold increase in congestive heart failure. Patients with HTN had a significant increase in the prevalence of cerebrovascular disease, stroke, and congestive heart failure. Patients with HTN and DM had a significant increase in all comorbidities. Smoking resulted in substantial increase of both peripheral vascular disease and cerebrovascular disease. Compared with nonsmoking patients with no DM or HTN, patients with DM and HTN and smoking had a 3-fold increase in the prevalence of peripheral vascular disease and a 3.5-fold increase in cerebrovascular disease (P < .001). CONCLUSIONS: We conclude that DM is a strong correlate of peripheral vascular disease, hypertension of cerebrovascular disease, and that there is a strong additive effect between DM, HTN, and smoking on both.

Aged↗

PubMed2001

Effects of atorvastatin versus fenofibrate on lipoprotein profiles, low-density lipoprotein subfraction distribution, and hemorheologic parameters in type 2 diabetes mellitus with mixed hyperlipoproteinemia.

Diabetic dyslipoproteinemia characterized by hypertriglyceridemia, low high-density lipoprotein (HDL) cholesterol, and often elevated low-density lipoprotein (LDL) cholesterol with predominance of small, dense LDL is a strong risk factor for atherosclerosis. It is unclear whether fibrate or statin therapy is more effective in these patients. We compared atorvastatin (10 mg/day) with fenofibrate (200 mg/day), each for 6 weeks separated by a 6-week washout period in 13 patients (5 men and 8 women; mean age 60.0+/-6.8 years; body mass index 30.0+/-3.0 kg/m2) with type 2 diabetes mellitus (hemoglobin A1c 7.3+/-1.1%) and mixed hyperlipoproteinemia (LDL cholesterol 164.0+/-37.8 mg/dl, triglycerides 259.7+/-107 mg/dl, HDL cholesterol 48.7+/-11.0 mg/dl) using a randomized, crossover design. Lipid profiles, LDL subfraction distribution, fasting plasma viscosity, red cell aggregation, and fibrinogen concentrations were determined before and after each drug. Atorvastatin decreased all LDL subfractions (LDL cholesterol, -29%; p <0.01) including small, dense LDL. Fenofibrate predominantly decreased triglyceride concentrations (triglycerides, -39%; p <0.005) and induced a shift in LDL subtype distribution from small, dense LDL (-31%) to intermediate-dense LDL (+36%). The concentration of small, dense LDL was comparable during therapy to both drugs (atorvastatin 62.8+/-19.5 mg/dl, fenofibrate 63.0+/-18.1 mg/dl). Both drugs induced an increase in HDL cholesterol (atorvastatin +10%, p <0.05; fenofibrate +11%, p = 0.06). In addition, fenofibrate decreased fibrinogen concentration (-15%, p <0.01) associated with a decrease in plasma viscosity by 3% (p <0.01) and improved red cell aggregation by 15% (p <0.05), whereas atorvastatin did not affect any hemorheologic parameter. We conclude that atorvastatin and fenofibrate can improve lipoprotein metabolism in type 2 diabetes. However, the medications affect different aspects of lipoprotein metabolism.

Aged↗