Neuropathies in adults with or without fat malabsorption.
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Adult↗
Biomedical subjects
H J Kayden
Publications and source records attributed to H J Kayden.
Absorption and transport of deuterium-substituted 2R,4'R,8'R-alpha-tocopherol in human lipoproteins.
Oral administration of a single dose of tri- or hexadeuterium substituted 2R,4'R,8'R-alpha-tocopheryl acetate (d3- or d6-alpha-T-Ac) to humans was used to follow the absorption and transport of vitamin E in plasma lipoproteins. Three hr after oral administration of d3-alpha-T-Ac (15 mg) to 2 subjects, plasma levels of d3-alpha-T were detectable; these increased up to 10 hr, reached a plateau at 24 hr, then decreased. Following administration of d6-alpha-T-Ac (15-16 mg) to 2 subjects, the percentage of deuterated tocopherol relative to the total tocopherol in chylomicrons increased more rapidly than the corresponding percentage in whole plasma. Chylomicrons and plasma lipoproteins were isolated from 2 additional subjects following administration of d3-alpha-T-Ac (140 or 60 mg). The percentage of deuterated tocopherol relative to the total tocopherol increased most rapidly in chylomicrons, then in very low density lipoproteins (VLDL), followed by essentially identical increases in low and high density lipoproteins (LDL and HDL, respectively) and lastly, in the red blood cells. This pattern of appearance of deuterated tocopherol is consistent with the concept that newly absorbed vitamin E is secreted by the intestine into chylomicrons; subsequently, chylomicron remnants are taken up by the liver from which the vitamin E is secreted in VLDL. The metabolism of VLDL in the circulation results in the simultaneous delivery of vitamin E into LDL and HDL.
Chylomicrons↗
Uptake of intact TPGS (d-alpha-tocopheryl polyethylene glycol 1000 succinate) a water-miscible form of vitamin E by human cells in vitro.
The mechanism by which TPGS (alpha-tocopheryl succinate esterified to polyethylene glycol 1000 [PEG 1000]) delivers tocopherol (vitamin E) was studied in human fibroblasts and erythrocytes and a human intestinal cell line, Caco-2. The total cellular tocopherol content of saponified samples of fibroblasts or Caco-2 incubated for 4 h with TPGS (4 mumol/L) increased 10-fold without an increase in the free tocopherol content of nonsaponified samples. A 24-h incubation resulted in a free tocopherol content of approximately 20%, suggesting that intracellular hydrolysis of ester bonds had occurred. The increase in total tocopherol content after a 4-h incubation with TPGS was temperature dependent; no change was measurable at 4 degrees C. Addition of metabolic inhibitors during incubation with TPGS at 37 degrees C did not prevent the increase. [14C]TPGS (synthesized from [14C]PEG 1000) was taken up by Caco-2 cells but [14C]PEG 1000 was not. The intracellular total tocopherol (pmol) equaled the [14C]TPGS (pmol), unequivocally demonstrating uptake of the intact TPGS molecule.
Carbon Radioisotopes↗
Effect of high doses of dietary vitamin E on the concentrations of vitamin E in several brain regions, plasma, liver, and adipose tissue of rats.
The object of this study was to assess the influence of high levels of dietary vitamin E on vitamin E concentrations in specific areas of the brain. Four-week-old male rats were fed vitamin E-deficient, control, and high-vitamin E (1,000 IU/kg) diets for 4 months. Concentrations of alpha-tocopherol in serum, adipose tissue, liver, cerebrum, cerebellum, and striatum were determined by liquid chromatography with fluorescence detection. In the high-vitamin E group, alpha-tocopherol concentrations in cerebrum, cerebellum, and striatum increased uniformly to 1.4-fold of values in controls; serum, adipose tissue, and liver attained even higher concentrations: 2.2-, 2.2-, and 4.6-fold, respectively, of control values. As observed before, brain levels of alpha-tocopherol were somewhat resistant to vitamin E deficiency, in contrast to the peripheral tissues.
Adipose Tissue↗
Isolated vitamin E deficiency in the absence of fat malabsorption--familial and sporadic cases: characterization and investigation of causes.
We observed four young adults, including three siblings, with a progressive neurologic disorder that developed over the first two decades. Electrophysiologic studies revealed mildly delayed nerve conduction, decreased amplitudes of sensory action potentials, and sensory delay in the posterior columns. Known causes of similar neurologic disorders were excluded. Although vitamin E deficiency was well documented, intestinal absorption and plasma lipoprotein transport of vitamin E were normal. Incubation studies in vitro failed to identify a plasma factor causing destruction of circulating vitamin E. There was no clinical or laboratory evidence of steatorrhea caused by gastrointestinal, hepatic, or pancreatic disease. Plasma lipoproteins, apolipoprotein B, and adipose tissue fatty acid composition were normal. Oral vitamin E therapy restored serum levels to normal and caused neurologic improvement in two patients. We postulate that an inherited defect in hepatocyte secretion of vitamin E into lipoproteins may account for this disorder, which occurs in sporadic cases as well as in siblings.
Absorption↗
Lack of tocopherol in peripheral nerves of vitamin E-deficient patients with peripheral neuropathy.
Vitamin E deficiency is often associated with symptoms of a peripheral neuropathy. To evaluate whether vitamin E deficiency affects the vitamin E content of the peripheral nervous system, we measured the alpha-tocopherol content in biopsy specimens of sural nerve and adipose tissue from 5 patients with symptomatic vitamin E deficiency (2 with homozygous hypobetalipoproteinemia and 3 with familial isolated vitamin E deficiency) and 34 control patients with neurologic diseases without vitamin E deficiency. A significant reduction in tissue tocopherol content was present in the vitamin E-deficient patients, as compared with the controls, both in sural nerves (1.8 +/- 1.2 vs. 20 +/- 16 ng per microgram of cholesterol [P less than 0.001], or 7.7 +/- 5.4 vs. 64 +/- 44 ng per milligram of wet weight [P less than 0.01]) and in adipose tissue (46 +/- 43 vs. 222 +/- 111 ng per milligram of triglyceride [P less than 0.001]). Levels of tocopherol in adipose tissue were significantly correlated (P less than 0.001) with levels in peripheral nerves. The low tocopherol content of the nerves preceded histologic degeneration in three vitamin E-deficient patients, suggesting that the nerve injury resulted from the low nerve tocopherol content.
Adipose Tissue↗
Tocopherol distribution and intracellular localization in human adipose tissue.
Adipocytes, isolated from human adipose tissue, were disrupted and then centrifuged, resulting in three fractions: oil, interface between the oil and the hypotonic buffer (containing lipid droplets surrounded by unilamellar membranes), and pelleted portion (containing bilayer membranes, intracellular organelles, and debris). The ratios of tocopherol:cholesterol and tocopherol:triglyceride were similar for adipose tissue, adipocytes, oil, and interface. The bulk lipid (oil plus interface fractions) of the adipocytes contained 99% of the tocopherol, 98% of the triglyceride, and 91% of the cholesterol. The tocopherol:cholesterol ratio was nearly eightfold greater in the bulk lipid than in the bilayer membrane fraction. By use of radioactively labeled tocopherol and cholesterol, it was demonstrated that the isolation protocol did not alter the distribution of the intracellular lipids; furthermore, the tocopherol in the lipid droplet did not readily exchange. Thus, the majority of tocopherol in adipose tissue is located in the bulk-lipid stores.
Adipose Tissue↗
Polarized secretion of newly synthesized lipoproteins by the Caco-2 human intestinal cell line.
Lipoprotein secretion by Caco-2 cells, a human intestinal cell line, was studied in cells grown on inserts containing a Millipore filter (0.45 micron), separating secretory products from the apical and basolateral membranes into separate chambers. Under these conditions, as observed by electron microscopy, the cells formed a monolayer of columnar epithelial cells with microvilli on the apical surface and tight junctions between cells. The electrical resistances of the cell monolayers were 250-500 ohms/cm2. Both 14C-labeled lipids and 35S-labeled proteins were used to assess lipoprotein secretion. After a 24-hr incubation with [14C]oleic acid, 60-80% of the secreted triglyceride (TG) was in the basolateral chamber; 40% of the TG was present in the d less than 1.006 g/ml (chylomicron + VLDL) fraction and 50% in the 1.006 less than d less than 1.063 g/ml (LDL) fraction. After a 4-hr incubation with [35S]methionine, apolipoproteins were found to be major secretory products with 75-100% secreted to the basolateral chamber. Apolipoproteins B-100, B-48, E, A-I, A-IV, and C-III were identified by immunoprecipitation. The d less than 1.006 g/ml fraction was found to contain all of the major apolipoproteins, while the LDL fraction contained primarily apoB-100 and apoE; the HDL (1.063 less than d less than 1.21 g/ml) fraction principally contained apoA-I and apoA-IV. Mn-heparin precipitated all of the [35S]methionine-labeled apoB-100 and B-48 and a majority of the other apolipoproteins, and 80% of the [14C]oleic acid-labeled triglyceride, but only 15% of the phospholipid, demonstrating that Caco-2 cells secrete triglyceride-rich lipoproteins containing apoB. Secretion of lipoproteins was dependent on the lipid content of the medium; prior incubation with lipoprotein-depleted serum specifically reduced the secretion of lipoproteins, while addition of both LDL and oleic acid to the medium maintained the level of apoB-100, B-48, and A-IV secretion to that observed in the control cultures.
Apoproteins↗
Clinical, nutritional and biochemical consequences of apolipoprotein B deficiency.
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Adipose Tissue↗
Absorption of water-miscible forms of vitamin E in a patient with cholestasis and in thoracic duct-cannulated rats.
Oral administration of vitamin E (100 mg tocopherol X kg-1 X day-1) as tocopheryl polyethylene glycol 1000 succinate (TPGS) to a child with congenital hepatic cholestasis (unresponsive to oral administration of dl-alpha-tocopheryl acetate) promoted an increase of tocopherol in plasma and adipose tissue while tocopheryl acetate emulsified with medium chain triglycerides and polysorbate 80 (MCT-E) did not. alpha-Tocopherol absorption, quantitated in thoracic duct-cannulated rats receiving intraduodenal infusions of soybean oil and saline, was similar for TPGS, MCT-E, and dl-alpha-tocopheryl acetate; gamma-tocopherol absorption from soybean oil was not affected by the presence of the supplemental alpha-tocopherol. Following bile duct ligation in one rat, TPGS promoted the absorption of alpha-tocopherol while absorption of gamma-tocopherol from soybean oil was decreased 30 fold, demonstrating that TPGS, which forms a micellar solution, delivers alpha-tocopherol through the unstirred water layer to enterocytes, while free tocopherol (alpha or gamma) absorption requires the presence of bile salts.
Administration, Oral↗
Electrophysiologic features of abetalipoproteinemia: functional consequences of vitamin E deficiency.
We performed electrophysiologic testing in 10 patients with abetalipoproteinemia (ABL). Peripheral nerve studies implied an axonal disorder. Visual evoked potentials demonstrated prolonged P100 latency in three patients and abnormal electroretinograms in six. Somatosensory evoked potentials indicated dorsal column dysfunction in eight patients. Brainstem auditory evoked potentials were normal. Findings were consistent with the known neuropathology of ABL and of experimental vitamin E deficiency. Stabilization or improvement in electrophysiologic findings occurred with vitamin E supplementation. Neurophysiologic tests document retinal, central somatosensory and peripheral nerve lesions in vitamin E deficiency and provide an objective indication of response to treatment.
Abetalipoproteinemia↗
The presence of 5 alpha-sitostanol in the serum of a patient with phytosterolemia, and its biosynthesis from plant steroids in rats with bile fistula.
The presence of 5 alpha-sitostanol (24-ethyl-5 alpha-cholestan-3 beta-ol) in serum of a patient with the rare genetic disease phytosterolemia was confirmed. This study aimed at clarifying the pathway(s) for the formation of 5 alpha-sitostanol, by use of rats with bile fistula. 5 alpha-Sitostanol was formed only slowly from sitosterol, but readily from 24-ethyl-4-cholesten-3-one. Some conversion was also obtained with 7 alpha-hydroxysitosterol as precursor. In view of the low rate of 7 alpha-hydroxylation of sitosterol, however, a pathway from sitosterol to 5 alpha-sitostanol involving 7 alpha-hydroxysitosterol as intermediate is probably of small physiological importance. Intestinal microorganisms are not essential for the above conversions, since the 5 alpha-sitostanol was found in bile from bile fistula rats. 5 alpha-Sitostanol was converted to water soluble metabolites (bile acids) much more slowly than was cholestanol (5 alpha-cholestan-3 beta-ol), and was accumulated serum to a much larger extent.
Adolescent↗
The secretion of apolipoprotein E by human monocyte-derived macrophages.
The secretion of newly synthesized apolipoprotein E (apo E) by human monocyte-derived macrophages (HMD macrophages) was measured in the medium of cells which had been incubated for 24 h with or without either native or acetylated low-density lipoproteins (LDL or AcLDL, respectively), and subsequently with [35S]methionine in the presence of high-density lipoproteins (HDL, 350 micrograms/ml) for 24 h, by isolating the lipoprotein fraction by centrifugation for 48 h at a density adjusted with KBr to 1.21 g/ml (d = 1.21). The d less than 1.21 medium was subjected to sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) or precipitation with trichloroacetic acid (TCA). Fluorography of the gels demonstrated that the d less than 1.21 fraction of the medium contained one major labeled band, which migrated with an apparent molecular weight of approximately 35,000. Immunoprecipitation of the d less than 1.21 fraction showed that the labeled band was precipitated by anti-apo E, but not by anti-HDL. As the apo E band appeared to be the only labeled band in the d less than 1.21 fraction, the amount of apo E secreted by the cells was quantitated by scintillation counting of the TCA-precipitable radioactivity in the d less than 1.21 fraction as compared with that in the whole medium. The proportion of secreted apo E to the total secreted protein was similar whether the cells had been in culture for 3 or 16 days, but was increased if the cells had been incubated with LDL or AcLDL. The proportion of apo E of the secreted proteins was always more than 6% and was as much as 16% when the cells were preincubated with lipoproteins, suggesting that the increased cholesterol influx induced apo E secretion.
Acetylation↗
Bovine milk lipoprotein lipase transfers tocopherol to human fibroblasts during triglyceride hydrolysis in vitro.
Lipoprotein lipase appears to function as the mechanism by which dietary vitamin E (tocopherol) is transferred from chylomicrons to tissues. In patients with lipoprotein lipase deficiency, more than 85% of both the circulating triglyceride and tocopherol is contained in the chylomicron fraction. The studies presented here show that the in vitro addition of bovine milk lipoprotein lipase (lipase) to chylomicrons in the presence of human erythrocytes or fibroblasts (and bovine serum albumin [BSA]) resulted in the hydrolysis of the triglyceride and the transfer of both fatty acids and tocopherol to the cells; in the absence of lipase, no increase in cellular tocopherol was detectable. The incubation system was simplified to include only fibroblasts, BSA, and Intralipid (an artificial lipid emulsion containing 10% soybean oil, which has gamma but not alpha tocopherol). The addition of lipase to this system also resulted in the transfer of tocopherol (gamma) to the fibroblasts. Addition of both lipase and its activator, apolipoprotein CII, resulted in a further increase in the cellular tocopherol content, but apolipoprotein CII alone had no effect. Heparin, which is known to prevent the binding of lipoprotein lipase to the cell surface membrane, abrogated the transfer of tocopherol to fibroblasts without altering the rate of triglyceride hydrolysis. Thus, in vitro tocopherol is transferred to cells during hydrolysis of triglyceride by the action of lipase, and for this transfer of tocopherol to occur, the lipase itself must bind to the cell membrane.
Animals↗
Blind loop syndrome, vitamin E malabsorption, and spinocerebellar degeneration.
A 72-year-old man had severe malabsorption, progressive retinopathy, and spinocerebellar degeneration 32 years after gastric surgery, blind loop formation, and intestinal bacterial overgrowth. Clinical and pathologic features were typical of vitamin E deficiency; vitamin E was nearly undetectable in serum and profoundly low in adipose tissue. Vitamin E blood levels initially improved on treatment with antibiotics; after additional vitamin E supplementation, there was clinical improvement.
Absorption↗
Inhibition of cholesterol synthesis by mevinolin stimulates low density lipoprotein receptor activity in human monocyte-derived macrophages.
Mevinolin inhibited the incorporation of [14C]acetate into cholesterol by human monocyte-derived macrophages (HMD macrophages) when both mevinolin and [14C]acetate were added simultaneously to the culture medium. Longer incubation with mevinolin, 24 h, led to a marked increase in the degradation of [125I]low density lipoprotein (LDL) via the high affinity receptor for LDL by HMD macrophages. Furthermore, this increased LDL receptor activity in cells incubated for 24 h with mevinolin and lipoprotein-depleted serum (LPDS) led to a nearly 3-fold increase in the formation of cholesteryl esters when these cells were then incubated with LDL for 24 h. Continuous exposure to mevinolin did not result in a constant increase in LDL receptor activity. Cells exposed to mevinolin for 24 h on day 3 had increased LDL receptor activity, but continuous exposure to mevinolin with 5% human serum (HS) from day 3-9 resulted in degradation of [125I]LDL at the same rate as observed in cells incubated with 5% HS alone. Cholesterol synthesis from [14C]acetate was decreased in cells incubated for 24 h in 5% HS + mevinolin compared with 5% HS alone, and in 10% LPDS + mevinolin compared with 10% LPDS alone; however, cells incubated with LPDS + mevinolin synthesized cholesterol at higher rates than did cells cultured in 5% HS alone. Continuous culture with 5% HS + mevinolin for 5 days resulted in cholesterol synthesis at control levels. These data show that following inhibition of cholesterol synthesis by mevinolin, HMD macrophages maintain cholesterol homeostasis by increasing LDL receptor activity to obtain cholesterol from LDL.
Anticholesteremic Agents↗
Vitamin E is delivered to cells via the high affinity receptor for low-density lipoprotein.
The high affinity receptor for low-density lipoprotein (LDL) is demonstrated to function as a mechanism for delivery of vitamin E to cells. After incubation for 24 h with lipoprotein-depleted serum (which induces LDL receptor synthesis), and then incubation for 24 h with an increasing amount of LDL (from 10 to 250 micrograms of protein per ml), the tocopherol contents of normal fibroblasts increased in a saturable fashion from 19 to 103 ng of tocopherol per mg cell protein. In contrast, similarly incubated LDL receptor-negative fibroblasts (from a patient with the homozygous form of familial hypercholesterolemia) only increased from 18 to 39 ng of tocopherol per mg. Estimation of the amount of LDL degraded from the cellular tocopherol uptake by normal cells yielded values virtually identical to the actual values of protein degradation as measured using 125I-LDL.
Biological Transport↗
Reduced tocopherol content of B cells from patients with chronic lymphocytic leukemia.
The tocopherol content of lymphocytes, erythrocytes, and plasma from patients with chronic lymphocytic leukemia (CLL), hairy cell leukemia (HCL), and normal subjects was measured by a sensitive high performance liquid chromatographic method. Lymphocytes from patients with CLL had lower values of tocopherol (1.7 +/- 1.0 micrograms/10(9) cells) than lymphocytes from normal subjects (3.8 +/- 0.7 micrograms/10(9) cells). Mononuclear cells from patients with HCL had an increased tocopherol content of 6.2 +/- 1.0 micrograms/10(9) cells. Subfractionation of the lymphocytes from patients with CLL into T- and B-cell subgroups showed that the tocopherol content of T cells was the same as in normal subjects (4.1 +/- 0.5 micrograms/10(9) cells versus 3.5 +/- 1.2), but that the tocopherol content of the B cells was markedly reduced compared to normals (2.6 +/- 1.0 versus 6.0 +/- 1.3).
B-Lymphocytes↗