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Bovine Milk Lipoprotein Lipase Transfers Tocopherol to Human Fibroblasts During Triglyceride Hydrolysis in Vitro Maret G

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Bovine Milk Lipoprotein Lipase Transfers Tocopherol to Human Fibroblasts During Triglyceride Hydrolysis in Vitro Maret G Bovine Milk Lipoprotein Lipase Transfers Tocopherol to Human Fibroblasts during Triglyceride Hydrolysis In Vitro Maret G. Traber, Thomas Olivecrona, and Herbert J. Kayden Department ofMedicine, New York University School ofMedicine, New York 10016; University of Umea, Umea, Sweden Abstract vitamin E, have minimal or absent neurological abnormalities, but those who have not been supplemented have a progressive Lipoprotein lipase appears to function as the mechanism by which dietary vitamin E (tocopherol) is transferred from chy- degeneration of the peripheral nervous system resulting in ataxia and characteristic pathologic changes in the central lomicrons to tissues. In patients with lipoprotein lipase defi- nervous system (5). These neuropathologic changes have been more than 85% of both the and ciency, circulating triglyceride observed in patients with cholestatic liver disease in whom the tocopherol is contained in the chylomicron fraction. The studies in low to absent levels of bile salts in the intestine results in an presented here show that the vitro addition of bovine milk inability to absorb vitamin E (3). Oral supplementation with to in the of lipoprotein lipase (lipase) chylomicrons presence pharmacologic amounts of the vitamin (6), or or fibroblasts bovine albumin pagenteral human erythrocytes (and serum administration of the vitamin (when there is a complete resulted in the hydrolysis of triglyceride and the [BSAJ) the absence of intestinal bile) (7) results in the prevention of transfer of both acids and to the in the fatty tocopherol cells; further of the nervous system. The studies in absence of no in cellular was deterioration lipase, increase tocopherol these two groups ofpatients have demonstrated the importance The incubation was to include detectable. system simplified of bile acids and chylomicron formation for the absorption of and artificial emulsion only fibroblasts, BSA, Intralipid (an lipid dietary vitamin E and its transport in the plasma. The studies containing 10% soybean oil, which has gamma but not alpha described in this were undertaken in an to The addition of to this also resulted report effort describe tocopherol). lipase system how tocopherol is transferred from the plasma to the tissues. in the transfer of tocopherol (gamma) to the fibroblasts. is present in normal in all of the of both lipase and its activator, apolipoprotein CII, Tocopherol individuals Addition plasma lipoprotein fractions; no specific carrier has been in a further increase in the resulted cellular tocopherol content, reported for the vitamin (8). Previously, we have demonstrated but CHI alone had no effect. which is apoliprotein Heparin, that the tocopherol present in LDL or high density lipoprotein known to prevent the binding of lipoprotein lipase to the cell (HDL) readily transfers to erythrocytes, when incubated together surface membrane, abrogated the transfer of tocopherol to in vitro (9). Furthermore, we have recently reported that the fibroblasts without the rate of altering triglyceride hydrolysis. tocopherol present in LDL is delivered to fibroblasts via the Thus, in vitro tocopherol is transferred to cells during hydrolysis high affinity receptor for LDL (10). of the action of and for this transfer of triglyceride by lipase, In contrast to the ease with which tocopherol can exchange tocopherol to occur, the lipase itself must bind to the cell when it is present in LDL or HDL, the tocopherol present in membrane. VLDL exchanged poorly in the experimental system (9). In Introduction patients who are deficient in lipoprotein lipase (type I), >85% of the circulating tocopherol and triglyceride is confined to Vitamin E (alpha tocopherol) deficiency has been described in lipoproteins with densities <1.006 g/ml, presumably chylomi- patients with various lipid malabsorption syndromes, including: crons and VLDL (1). Lipoprotein lipase is known to hydrolyze abetalipoproteinemia (1, 2), cholestatic liver disease (3), and triglyceride to free fatty acids and transfer the fatty acids to short bowel syndrome (4). In 1967, Kayden recommended tissues (for review, see I 1). This enzyme can also mediate the dietary supplementation with vitamin E for patients with transfer of cholesteryl esters (12) or cholesteryl linoleyl ether abetalipoproteinemia (2). The malabsorption syndrome in (13) from triglyceride-rich lipoproteins to cells. Thus, we these genetically affected subjects is a result of their inability speculated that lipoprotein lipase might play a significant role to synthesize apolipoprotein B; these patients are thus unable in the distribution of tocopherol from chylomicrons to the to secrete chylomicrons, very low or low density lipoproteins tissues. We describe here our studies in tissue culture using (VLDL or LDL, respectively). Patients with abetalipoprotein- chylomicrons (from type I patients) or Intralipid (an artificial emia have low levels of circulating lipids, as well as low levels lipid emulsion) as substrate for bovine milk lipoprotein lipase of plasma tocopherol, despite supplemental vitamin E (1). (lipase), and either human fibroblasts or human erythrocytes However, those patients, who have been supplemented with as acceptor cells. This work has appeared in abstract form in 1984. Fed. Proc. 43:824. Methods Address reprint requests to Dr. Kayden, Department of Medicine, New York University School of Medicine, New York 10016. Cell culture. Fibroblasts were obtained from the Genetic Cell Repository Received for publication 30 May 1984 and in revised form 28 (Camden, NJ). The normal cells used were GM0144 and the cells of January 1985. the homozygote for familial hypercholesterolemia were GM0486. Cells were grown in 20% fetal calf serum in Dulbecco's modified Eagle J. Clin. Invest. medium (DMEM)' with penicillin and streptomycin at 37°C with 5% © The American Society for Clinical Investigation, Inc. 0021-9738/85/05/1729/06 $ 1.00 1. Abbreviations used in this paper: DMEM, Dulbecco's modified Volume 75, May 1985, 1729-1734 Eagle medium. Lipoprotein Lipase Transfers Tocopherol to Cells 1729 CO2. Confluent monolayers of cells in 25 cm2 flasks were used for the protein by the method of Lowry et al. (18), for scintillation counting incubations, which are described below. to measure the uptake of labeled fatty acids, and for measurement of Isolation ofchylomicrons. Patients with hypertriglyceridemia (serum tocopherol content following saponification (19). Briefly, the cells were triglycerides in excess of 1,000 mg/dl), normal levels of apolipoprotein saponified at 70'C with alcoholic KOH in the presence of 1% ascorbic CII, and absent lipoprotein lipase activity after intravenous injection acid for 30 min, then extracted with hexane. The hexane was aliquoted, of heparin were donors of "chylomicrons." Plasma (30 ml) from each dried down, and the residue dissolved in methanol with 1% ascorbic patient was isolated from whole blood, then spun without change in acid. The alpha and gamma tocopherol contents of the methanol were density for 1 h at 100,000 g. The d < 1.006 g/ml layer was isolated, measured by injecting the methanol using the Waters Intelligent and is called "chylomicrons" for the purposes of these experiments. Sample Processor into the high performance liquid chromatography Preparation oferythrocytes. Erythrocytes were isolated from whole system, and detected by fluoresence (excitation, 205 nm; emission, blood donated by normal volunteers by centrifugation for 10 min at 340 nm) as described previously (19). As little as 1 ng of either alpha 2,000 rpm. The plasma and buffy coat were discarded and the or gamma tocopherol could be measured accurately following this erythrocytes washed three times with phosphate-buffered saline, pH protocol. 7.4, as previously described (14). Triglyceride hydrolysis. For the measurement of the free fatty acid Preparation of radioactive intralipid. Glyceryl-tri(stearate 9,10-3H) content of the medium, the medium was poured directly into 15 ml (Nuclear Chicago Corp., Des Plaines, IL) was plated onto silica gel G, of stopping solution (heptane/chloroform/methanol [1:1.25:1.4] con- the plate developed in petroleum ether/ethyl ether/acetic acid (83:16: taining ["C]oleic acid, -8 X 106 cpm/ml), and shaken vigorously for 1), the triglyceride fraction identified, and the silica gel scraped and 1 min, as described by Belfrage and Vaughan (20). Then, 1 ml of 1 N extracted with chloroform. An aliquot of the chloroform containing NaOH was added, and the samples were shaken for I h. At the end -2 X 10' cpm was dried down in a scintillation vial, then -5 ml of the extraction period, the tubes were spun in a centrifuge for 10 Intralipid was added, and the sample stirred overnight at room min at 2,500 rpm to separate the two layers. An aliquot (6 ml) of the temperature. Approximately 10% of the radioactivity was exchanged upper methanol/water layer was acidified with 100 Ml concentrated onto the Intralipid by this procedure. HCI, and then extracted with heptane (6 ml) by shaking for I h. Bovine milk lipoprotein lipase. The lipase was isolated as described Following the extraction period, 2.5 ml of 50% TCA was added, and previously (15). It was kept frozen at -60'C and defrosted on ice then the tubes spun as before. (The TCA is added to precipitate the immediately before use. large amounts of albumin present, which otherwise remained at the Cell incubation protocol. Fibroblasts (washed once in the flask with heptane/methanol interface. Any fatty acids which might be trapped DMEM) or erythrocytes (isolated as described above) were incubated by the TCA are corrected for by the recovery of the internal standard.) for I h with chylomicrons with or without lipase in the presence of Aliquots of the heptane were taken for counting (100 tl) and for 7.5% bovine serum albumin (BSA) in DMEM at pH 7.4 for Table I. methylation (5 ml). For Fig. 1, the standard protocol (described below) was used with the To methylate the samples, the heptane was dried down and 0.5 ml addition of chylomicrons. of 5% H2S04 in methanol with 1% benzene was added and the samples The standard protocol was carried out with defined components.
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