The metabolism of very low density lipoprotein proteins I. Preliminary in vitro and in vivo observations

Bilheimer, David W.; Eisenberg, Shlomo; Levy, Robert I.

doi:10.1016/0005-2760(72)90034-3

Cited by 1,789 publications

(440 citation statements)

References 20 publications

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“…The concentration of the LDL solution was determined by measuring apoB, according to the method of Lowry et al (1951) with bovine serum albumin (BSA) as standard. For in vitro experiments, LDL was labelled using the ['5l]iodine monochloride method as described in detail by Bilheimer et al (1972). For in vivo experiments, LDL was labelled with '1I-tyrammne cellobiose ('-I-TC) as described previously (Versluis et al, 1996).…”

Section: Isolation and Radioiodination Of Ldlmentioning

confidence: 99%

Low-density lipoprotein receptor-mediated delivery of a lipophilic daunorubicin derivative to B16 tumours in mice using apolipoprotein E-enriched liposomes

Versluis¹,

Rensen²,

Rump³

et al. 1998

Br J Cancer

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Summary Many tumours express relatively high levels of low-density lipoprotein (LDL) receptors on their membranes. The LDL receptor is, therefore, an attractive target for the selective delivery of antineoplastic drugs to tumour cells. We reported previously on the synthesis of small apolipoprotein E (apoE)-containing liposomes that behave in vivo in a very similar way to native LDL. In this study, we (LAD). Tissue distribution studies showed that LAD-loaded apoE liposomes were taken up and processed by the major LDL receptor-expressing organs (i.e. adrenals, liver and spleen). Of all other tissues, the tumour showed the highest uptake. The distribution pattems of LAD-loaded apoE liposomes and native LDL in the tumour-bearing mice were very similar, which supports the role of the LDL receptor in the disposition of the prodrug-loaded particles. The disposition of LAD followed the pattem of the liposomal carrier. We conclude that apoE liposomes enable LDL receptor-mediated specific delivery of antineoplastic (pro)

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Section: Isolation and Radioiodination Of Ldlmentioning

confidence: 99%

Low-density lipoprotein receptor-mediated delivery of a lipophilic daunorubicin derivative to B16 tumours in mice using apolipoprotein E-enriched liposomes

Versluis¹,

Rensen²,

Rump³

et al. 1998

Br J Cancer

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“…After the recording of surface radioactivity and pressure had stabilized (5-10 mm), 25 ~1 heparin (1 mg/ml), 100 ~1 fatty acid-free bovine serum albumin (1 mg/ml) and various amounts of apolipoprotein C-II (1 mg/ml in 6 M guanidine), as indicated, were added to the subphase at 1-min intervals. [18]; the '251-labelled protein had a specific radioactivity of 214 dpm/ng. '251-labelled apolipoprotein C-II enhanced the activity of lipoprotein lipase to the same extent as the unlabelled apoprotein.…”

Section: Analytic Proceduresmentioning

confidence: 99%

Effect of monolayer lipid structure and composition on the lipoprotein lipase-catalyzed hydrolysis of triacylglycerol

Demel

Dings

Jackson

1984

Biochimica et Biophysica Acta (BBA) - Lipids and Lipid Metaboli

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The effect of lipid composition and structure on the lipoprotein lipase-catalyzed hydrolysis of triacylglycerols was determined in a monolayer system consisting of purified bovine milk lipoprotein lipase and fatty acid-free albumin. In a monolayer of dioleoylphosphatidylcholine containing l-6 mol% of either tri[ "C]oleoylglycerol or tri[ "C]palmitoylglycerol, lipoprotein lipase catalyzed the hydrolysis of the unsaturated triacylglycerol at a higher rate than the saturated lipid and in either the presence or absence of apolipoprotein C-II, the activator protein for the enzyme. For example, with 3 mol% triacylglycerol and in the presence of apolipoprotein C-II, the rate of the lipoprotein lipase-catalyzed hydrolysis of tri['4C]oleoylglycerol was 27 pmol oleic acid produced/h per mg enzyme vs. 12 prnol for tri[14C]palmitoylglycerol. The effect of phospholipid fatty acyl chain length and unsaturation/saturation, polar head group and surface density on the lipoprotein lipase-catalyzed hydrolysis of tri[ 14C]oleoylglycerol was determined. The rate of enzyme hydrolysis of triacylglycerol was similar whether the phospholipid was a diester or diether lipid or the polar head group was ethanolamine or choline. In general, phospholipids with shorter and unsaturated fatty acyl chains gave higher rates of lipoprotein lipase hydrolysis of triacylglycerol than the corresponding longer and saturated lipids. However, with all phospholipids tested, the rate of enzyme hydrolysis decreased with increasing surface density. Lipoprotein lipase showed no activity toward triacylglycerol in a monolayer of sphingomyelin; addition of dioleoylphosphatidylcholine to the monolayer enhanced the rate of enzyme catalysis. Cholesterol (50 mol%) in a dipalmitoylphosphatidylcholine monolayer increased the rate of the lipoprotein lipase-catalyzed hydrolysis of tri[ "C]oleoylglycerol, whereas cholesterol decreased the rate in a dioleoylphosphatidylcholine monolayer. The effect of phospholipid structure and surface density on lipoprotein lipase activity could not be accounted for by the amount of apolipoprotein C-II which was present at the interface. Based on these findings and other reports in the literature, we suggest that the catalytic activity of lipoprotein lipase toward tri['4C]oleylglyceroI in various monolayers is dependent on the conformation or appropriate physical state of the triacylglycerol substrate at the lipid interface.

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“…LDL was radiolabeled by the iodine monochloride method [22] as modified for lipoproteins [23]. Labeling efficiency ranged from 22 to 38% and less than 3% of the label remained in the organic phase of a chloroform/methanol (2:1, v/v) extraction.…”

Section: Lipoprotein Preparationmentioning

confidence: 99%

Metabolism of low-density lipoproteins by cultured hepatocytes from normal and homozygous familial hypercholesterolemic subjects

Hoeg

Edge

Demosky

et al. 1986

Biochimica et Biophysica Acta (BBA) - Lipids and Lipid Metaboli

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The profoundly elevated concentrations of low-density lipoproteins (LDL) present in homozygous familial hypercholesterolemia lead to symptomatic cardiovascular disease and death by early adulthood. Studies conducted in nonhepatic tissues demonstrated defective cellular recognition and metabolism of LDL in these patients. Since mammalian liver removes at least half of the LDL in the circulation, the metabolism of LDL by cultured hepatocytes isolated from familial hypercholesterolemic homozygotes was compared to hepatocytes from normal individuals. Fibroblast studies demonstrated that the familial hypercholesterolemic subjects studied were LDL receptor-negative (less than 1% normal receptor activity) and LDL receptor-defective (18% normal receptor activity). Cholesterol-depleted hepatocytes from normal subjects bound and internalized 125 I-labeled LDL (B max = 2.2 μg LDL/mg cell protein). Preincubation of normal hepatocytes with 200 μg/ml LDL reduced binding and internalization by approx. 40%. In contrast, 125 I-labeled LDL binding and internalization by receptor-negative familial hypercholesterolemic hepatocytes was unaffected by cholesterol loading and considerably lower than normal. This residual LDL uptake could not be ascribed to fluid phase endocytosis as determined by [ 14 C]sucrose uptake. The residual LDL binding by familial hypercholesterolemia hepatocytes led to a small increase in hepatocyte cholesterol content which was relatively ineffective in reducing hepatocyte 3-hydroxy-3-methylglutaryl-CoA reductase activity. Receptordefective familial hypercholesterolemia hepatocytes retained some degree of regulatable 125 Ilabeled LDL uptake, but LDL uptake did not lead to normal hepatocyte cholesterol content or 3-hydroxy-3-methylglutaryl-CoA reductase activity. These combined results indicate that the LDL receptor abnormality present in familial hypercholesterolemia fibroblasts reflects deranged hepatocyte LDL recognition and metabolism. In addition, a low-affinity, nonsaturable uptake process for LDL is present in human liver which does not efficiently modulate hepatocyte cholesterol content or synthesis.

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The metabolism of very low density lipoprotein proteins I. Preliminary in vitro and in vivo observations

Cited by 1,789 publications

References 20 publications

Low-density lipoprotein receptor-mediated delivery of a lipophilic daunorubicin derivative to B16 tumours in mice using apolipoprotein E-enriched liposomes

Low-density lipoprotein receptor-mediated delivery of a lipophilic daunorubicin derivative to B16 tumours in mice using apolipoprotein E-enriched liposomes

Effect of monolayer lipid structure and composition on the lipoprotein lipase-catalyzed hydrolysis of triacylglycerol

Metabolism of low-density lipoproteins by cultured hepatocytes from normal and homozygous familial hypercholesterolemic subjects

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