New developments in fat emulsions.
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Fat Emulsions, Intravenous↗
Biomedical subjects
R J Deckelbaum
Publications and source records attributed to R J Deckelbaum.
In vitro remodelling of plasma lipoproteins in whole plasma by lipoprotein lipase in primary and secondary hypertriglyceridaemia.
In patients with familial lipoprotein lipase deficiency (FLPL-d) and glycogen storage disease type I (GSD-I), hypertriglyceridaemia (1445 +/- 247 and 1082 +/- 312 mg dl-1, n = 5 per group) was associated primarily with reduced extrahepatic lipoprotein lipase (LPL) activity (0.33 +/- 0.33 and 1.69 +/- 0.38 mumol FFA ml-1 h-1) when compared with controls (4.83 +/- 0.90). Hypercholesterolaemia was characterized by elevated LDL cholesterol (191 +/- 30 and 344 +/- 34 vs. 115 +/- 5 mg dl-1 in controls P less than 0.01) and low HDL cholesterol (12 +/- 2 and 22 +/- 2 vs. 56 +/- 3 in controls, P less than 0.001). In order to ascertain the role of LPL in the interconversion and remodelling of lipoproteins in these disorders, we analysed lipid and lipoprotein profiles before and following in vitro incubation of patient plasma with purified milk LPL (EC 3.1.1.34) for 6 h at 37 degrees C. The efficiency of exogenous LPL in vitro was demonstrated by the extent of hydrolysis of chylomicrons and of VLDL-TG in both groups. Concomitant with the disappearance of TG-rich lipoprotein particles, a consistent per cent increment of IDL (99.2 +/- 30.8 and 43.9 +/- 70.5), LDL (152.8 +/- 36.2 and 137.0 +/- 36.1) and of HDL2 (144.8 +/- 29.4 and 99.8 +/- 18.7) was observed in both groups of patients. The enhancement of the latter fractions contrasted with the decline of HDL3 mass concentration (25.4 +/- 7.7 and 51.4 +/- 5.8%), suggesting that a major shift of HDL3----HDL2 occurs following in vitro lipolysis by LDL. Simultaneous compositional and morphological changes of individual lipoprotein particles were noted, confirming the dynamic movement and exchange of neutral lipids and proteins. Specificity of LPL results was demonstrated by experiments in which incubation of the whole plasma at 37 degrees C without exogenous lipolytic enzyme did not cause any substantial changes. The present study, therefore, demonstrates a correction of the major lipoprotein abnormalities associated with FLPL-d and GSD-I by exogenous LPL. No substantial difference was noted between primary (FLPL-d) and secondary (GSD-I) hyperlipidaemias. These studies allow us to conclude that a simple in vitro system, utilizing an exogenous source of LPL and plasma from patients, may serve as a suitable model for the study of the metabolic relationships of lipoproteins. However, in view of the fact that the extent of lipolysis achieved in vitro did not differ between FLPL-d and GSD-I, it may not be able to separate primary from secondary hyperlipaemias.
Adolescent↗
Nutrition, the child and atherosclerosis. A commentary.
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Adolescent↗
Characterization of a cDNA encoding a cysteine-rich cell surface protein located in the flagellar pocket of the protozoan Trypanosoma brucei.
We have characterized a cDNA encoding a cysteine-rich, acidic integral membrane protein (CRAM) of the parasitic protozoa Trypanosoma brucei and Trypanosoma equiperdum. Unlike other membrane proteins of T. brucei, which are distributed throughout the cell surface, CRAM is concentrated in the flagellar pocket, an invagination of the cell surface of the trypanosome where endocytosis has been documented. Accordingly, CRAM also locates to vesicles located underneath the pocket, providing evidence of its internalization. CRAM has a predicted molecular mass of 130 kilodaltons and has a signal peptide, a transmembrane domain, and a 41-amino-acid cytoplasmic extension. A characteristic feature of CRAM is a large extracellular domain with a roughly 66-fold acidic, cysteine-rich 12-amino-acid repeat. CRAM is conserved among different protozoan species, including Trypanosoma cruzi, and CRAM has structural similarities with eucaryotic cell surface receptors. The most striking homology of CRAM is to the human low-density-lipoprotein receptor. We propose that CRAM functions as a cell surface receptor of different trypanosome species.
Amino Acid Sequence↗
Response to diet and cholestyramine in a patient with sitosterolemia.
In this report, an 11-year-old boy with diffuse tendinous and tuberous xanthomatosis and a plasma sterol concentration of 555 mg/dL, consisting primarily of cholesterol, is described. Three months after changing from an unrestricted diet to a cholesterol-lowering diet, his plasma sterol concentration decreased to 221 mg/dL. Because of the degree and rapidity of his response to diet, sitosterolemia was suspected. According to results of capillary gas-liquid chromatography of his plasma sterols, there was a sitosterol concentration of 31.3 mg/dL (normal less than 1.0 mg/dL), establishing the diagnosis of sitosterolemia. Addition of cholestyramine therapy (8 g/d) to a low sterol diet further lowered his plasma sterol concentration to 173 mg/dL and led to complete regression of all tuberous xanthomata. Tendinous xanthomata regressed at a slower rate. These findings show that the diagnosis of sitosterolemia should be suspected in severely hypercholesterolemic children (total cholesterol greater than 400 mg/dL) whose plasma cholesterol level is highly responsive to dietary manipulation. The rapid and sustained lowering of plasma cholesterol and regression of xanthomata after treatment with diet and cholestyramine suggest that sitosterolemia is a treatable cause of premature atherosclerosis.
Arteriosclerosis↗
Exclusion of linkage between the human apolipoprotein B gene and abetalipoproteinemia.
Abetalipoproteinemia (ABLP) is a rare autosomal recessive disease characterized by a lack of plasma apolipoprotein B (apo B). In this report, the hypothesis that ABLP is due to rare mutations in the apo B gene was tested. A total of eight ABLP families were studied. Apo B gene RFLPs were used to establish the haplotypes of the apo B alleles in family members. LOD score analysis was used to study the linkage between the apo B alleles and ABLP. These families were categorized arbitrarily as class I, II, III, or IV because of differences in the results derived from both haplotyping and LOD score analysis. In a class I family, affected siblings, who on the basis of the hypothesis would be expected to have the same apo B alleles, had different ones. LOD score analysis of this family gave an infinite negative number at a recombination fraction (theta) of zero. In two class II families, probands who were the result of consanguineous marriages and who, on the basis of the hypothesis, should be homozygotes for a defective apo B allele, were heterozygotes at this locus. The sum of the LOD scores from these two families was -1.7 at theta = 0. In one class III family, a parent was apparently homozygous for a particular apo B allele and yet not affected. This also contributed negatively to the LOD score. In four class IV families, disease inheritance was compatible with segregation of the apo B alleles. This, however, was not statistically significant (LOD score = 0.97 at theta = 0).(ABSTRACT TRUNCATED AT 250 WORDS)
Abetalipoproteinemia↗
Unesterified fatty acids inhibit the binding of low density lipoproteins to the human fibroblast low density lipoprotein receptor.
Micromolar concentrations of oleate were found to inhibit reversibly the binding of low density lipoprotein (LDL) to the human fibroblast LDL receptor. The decrease in LDL binding caused a parallel reduction of both 125I-LDL uptake and degradation at 37 degrees C. At 4 degrees C, oleate was also found to displace 125I-LDL already bound to the LDL receptor. The effect of oleate was rapid, reaching 70-80% of maximum displacement with 5-10 min of incubation, and was closely correlated to oleate-albumin molar ratios. Partition analysis of unesterified fatty acids between cells and LDL showed that the inhibitory effect of oleate resulted mainly from an interaction of unesterified fatty acids with the cell surface rather than with the LDL particles. Using different unesterified fatty acids and fatty acid analogs, we found that the inhibitory effect was modulated by both the length and the conformation of the monomeric carbon chain and was directly dependent on the presence of a negative charge on the carboxylic group. At 4 degrees C, the inhibitory effect of oleate never exceeded half of maximum binding capacity. This limitation was associated with the ability of oleate to interact only with part of the population of LDL receptors which spontaneously recycles in the absence of ligand, as demonstrated by the fact that oleate did not induce any reduction of LDL binding after cell treatment with monensin in the absence of LDL. Our results indicate that unesterified fatty acids could participate in the control of LDL catabolism in vivo by direct modulation of the ability of LDL receptor to bind LDL.
Cells, Cultured↗
Hypobetalipoproteinemia due to an apolipoprotein B gene exon 21 deletion derived by Alu-Alu recombination.
We report the molecular defect in an individual with homozygous hypobetalipoproteinemia. A unique TaqI restriction fragment length polymorphism was found in the midportion of the apolipoprotein B (apoB) gene using the genomic probe, pB51. The probe, which identifies TaqI fragments of 8.4 and 2.8 kilobases (kb) in normal individuals, hybridized to a single 11-kb fragment in the proband. The parents of the proband showed all three TaqI fragments, implying that they are heterozygotes for the mutant apoB allele. In this family, the mutant allele cosegregated with low total cholesterol levels and formal linkage analysis gave a decimal logarithm of the ratio score of 3.3 at a recombination frequency of 0. The polymorphic TaqI site was localized to an EcoRI fragment of 4 kb in normal individuals. The corresponding fragment in the proband was 3.4 kb, suggesting a 0.6-kb deletion in the mutant allele. Both the normal 4-kb EcoRI fragment and the mutant 3.4-kb EcoRI fragment were cloned and sequenced. In the normal allele, the 4-kb EcoRI fragment extends from intron 20 to 23. Exon 21 is flanked by Alu sequences that are in the same orientation. The mutant allele had a 694-bp deletion in this region which included a small part of the Alu sequence in intron 20, the entire exon 21, and most of the Alu sequence in intron 21. The polymorphic TaqI site, which lies within the Alu sequence in intron 21, was absent in the proband as a result of the deletion. The deletion of exon 21 results in a frame shift mutation and the introduction of a stop codon. Translation of the encoded mRNA would yield a prematurely terminated protein. This mutant apoB protein would be 1085 amino acids long with the 73 carboxyl-terminal residues out of frame. We postulate that the deletion of exon 21 is the consequence of a crossover event between the Alu sequences in introns 20 and 21 resulting in nonreciprocal exchange between two chromosomes.
Alleles↗
Intralipid infusion into humans reduces in vitro platelet aggregation and alters platelet lipid composition.
Intralipid (Kabi Vitrum Inc, Alameda, CA) infusion into normal volunteers results in substantial elevation in serum triglyceride, phospholipids, and free cholesterol concentrations. Platelet aggregation induced in vitro in platelet-rich plasma by collagen or ADP was significantly reduced by up to 40% and 45%, respectively, during the infusion period but returned to preinfusion levels 18 hours after the end of the infusion. In parallel, platelet lipid composition was also affected. Platelet free cholesterol content was reduced by up to 20% during the infusion of Intralipid, whereas platelet triglyceride and phospholipid contents increased by 3.5-fold and twofold, respectively. Eighteen hours after the end of the infusion, both platelet cholesterol and triglyceride returned to preinfusion levels, but platelet phospholipid was still elevated. Both components of Intralipid (liposomes and triglyceride-phospholipid particles) were able to decrease in vitro platelet aggregation and platelet cholesterol content. Our results demonstrate decreased platelet function induced by Intralipid infusion into humans, which was associated with reduced platelet cholesterol content. These results suggest possible antiatherogenic effects of infusing Intralipid in humans.
Adenosine Diphosphate↗
Hypocholesterolemia in childhood.
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Adolescent↗
Plasma lipid and plasma lipoprotein concentrations in low birth weight infants given parenteral nutrition with twenty or ten percent lipid emulsion.
Because 10% and 20% intravenously administered lipid emulsions (intralipid preparations) differ in their phospholipid/triglyceride ratio (0.12 and 0.06, respectively), 28 low birth weight infants requiring parenteral nutrition for at least 1 week were selected at random to receive either emulsion to determine the effects on plasma lipids and lipoproteins. Triglyceride intake was progressively increased to reach 2 gm/kg per day between days 4 and 7. During that period, all plasma lipids in samples taken 6 hours after infusion were higher in the 10% intralipid group. In comparison with day 0 values, triglyceride concentrations decreased (63 +/- 7 to 45 +/- 4 mg/dl; p less than 0.05) in the 20% group. Cholesterol levels increased in both groups, but the rise was more than twofold higher in the 10% group. Phospholipid increase was approximately 25% in the 20% group but more than 125% in patients receiving the 10% emulsion (p less than 0.005). The changes in plasma cholesterol and phospholipid levels were almost entirely in low-density lipoproteins. After 7 days, eight infants from each group were given the alternate emulsion, which resulted in a reversal of lipid patterns in each patient. We conclude that the higher phospholipid intake in 10% than in 20% intralipid is associated with higher plasma triglyceride concentrations and leads to accumulation of cholesterol and phospholipids in low-density lipoproteins. Emulsions with lower phospholipid content may be preferable for low birth weight infants and perhaps other patient populations with impaired removal of parenteral fat emulsions.
Cholesterol, HDL↗
Asymptomatic giardiasis in children.
Giardia lamblia infection was identified in 33 of 89 (37%) 3-month-old to 3-yr-old children who were followed with monthly stool examinations for up to 12 months in a day care center. The infection was mainly asymptomatic and usually associated with prolonged carriage of the parasite. There were no significant differences for height and weight achievements and mean hemoglobin values between Giardia-positive and Giardia-negative children. However, Giardia-positive children tended to achieve higher weight and height for age than Giardia-negative children; weight for age was above the 50th percentile in 69% of Giardia-positive vs. 40% of Giardia-negative children (alpha = 0.01). Giardia-positive children tended to have fewer symptoms related to the gastrointestinal and respiratory tracts as recorded by a weekly questionnaire. Lactase deficiency was detected by breath hydrogen testing in 8 of 26 Giardia-positive vs. only 1 of 21 Giardia-negative children (P less than 0.02). Healthy day care children with asymptomatic Giardia infection show no disadvantage and perhaps even an advantage in nutritional status and freedom from other illnesses.
Body Height↗
Inhibition of cholesteryl ester transfer protein activity by monoclonal antibody. Effects on cholesteryl ester formation and neutral lipid mass transfer in human plasma.
We have employed a neutralizing monoclonal antibody, prepared against the Mr 74,000 cholesteryl ester transfer protein (CETP), to investigate the regulation of lecithin:cholesterol acyltransferase (LCAT) activity by cholesteryl ester (CE) transfer, and also to determine which lipoproteins are substrates for LCAT in human plasma. The incubation of normolipidemic plasma led to transfer of CE from HDL to VLDL, and of triglycerides from VLDL to LDL and HDL. This net mass transfer of neutral lipids between the lipoproteins was eliminated by the monoclonal antibody. However, CE transfer inhibition had no effect on the rate of plasma cholesterol esterification in plasma incubated from 10 min to 24 h at 37 degrees C. In the absence of CE transfer, HDL and LDL exhibited cholesterol esterification activity, whereas VLDL did not. The rate of CE formation in HDL was three to four times greater than in LDL during the first hour of incubation, but CE formation in HDL decreased after 6-8 h, while that in LDL continued. Thus, (a) the Mr 74,000 CETP is responsible for all neutral lipid mass transfer in incubated human plasma, (b) the rate of CE formation in plasma is not regulated by CE transfer from HDL to other lipoproteins, and (c) HDL is the major initial substrate for LCAT; LDL assumes a more significant role only after prolonged incubation of plasma.
Adult↗
Macrophage cholesterol removal by triglyceride-phospholipid emulsions.
Phospholipid liposomes were previously shown to mobilize cholesterol from cultured macrophage foam cells. Because Intralipid, a clinically available triglyceride-phospholipid emulsion, contains both phospholipid liposomes and triglyceride-emulsion particles, we sought to study its effect on macrophage cholesterol mobilization. Following an 18h incubation of J774 macrophages in serum-free medium supplemented with Intralipid, cholesteryl ester content decreased by up to 50% in previously cholesterol-loaded cells, and by 25% in non-loaded cells. Both components of Intralipid, liposomes and emulsion particles, independently caused reductions in cellular cholesteryl ester. We conclude that clinically available triglyceride-phospholipid emulsions can mobilize macrophage cholesterol in vitro.
Animals↗
Neutral lipid transfer and lipolysis convert high molecular weight LDL from cholesterol-fed nonhuman primates towards normal: a molecular analysis.
In cynomolgus monkeys (Macaca fascicularis) fed an atherogenic diet, large, cholesterol ester-rich LDL (Mr greater than 3.5.10(6] are found at the same time that the plasma triacylglycerol levels are low. We studied whether the presence of higher concentrations of triacylglycerol-rich lipoproteins (VLDL) during in vitro incubations would allows depletion from LDL of cholesterol ester and a decreased LDL molecular weight. Three high Mr LDL (Mr = (3.7-4.8).10(6)), rich in cholesterol ester (50 +/- 1.4% by weight), were isolated from three animals by zonal ultracentrifugation, and were then incubated with human VLDL at 37 degrees C for 18 h in lipoprotein-deficient human plasma containing neutral lipid transfer activity. After incubation, modified LDL (M-LDL) was isolated by zonal ultracentrifugation. M-LDL was triacylglycerol-rich (36 +/- 5% by weight) and cholesterol ester-poor (20 +/- 3%), and cholesterol ester had transferred into VLDL. Purified lipoprotein lipase was added to the M-LDL, and triacylglycerol was hydrolyzed. The size of the post-lipolysis M-LDL (Mp-LDL) particles became smaller (mean diameters of 253 A and 228 A for two native LDLs and 215 A and 193 A for Mp-LDL, respectively). Both analytical and zonal ultracentrifugation showed Mp-LDL to be more dense than native LDL. Estimated molecular weights for Mp-LDL were 40%-50% less than that of the original LDL, and fell within the molecular weight range for normal human and monkey LDL. Lipid exchanges, but not apoprotein transfers, were responsible for LDL remodelling, as supported by three separate methods of analysis. Cholesterol ester losses accounted for about two-thirds of the molecular weight decrease. These in vitro results suggest that cholesterol ester enrichment of apoprotein B lipoprotein particles can be reversed by providing adequate levels of VLDL in the presence of neutral lipid transfer processes and lipolytic activity.
Animals↗
Cryptosporidium, malnutrition, and chronic diarrhea in children.
Cryptosporidium was found in the stools of 13.5% of 221 children hospitalized with diarrhea. It was the single most prevalent pathogen isolated. Children with Cryptosporidium-positive stools were significantly more malnourished than children in whom Cryptosporidium was not detected. Children with more severe malnutrition (ie, less than 50% of their expected weight) and with Cryptosporidium in their stools had a significantly longer duration of diarrhea than similarly malnourished children without Cryptosporidium (63 vs 32 days, respectively). In 77 better-nourished outpatients with diarrhea, Cryptosporidium was found in only 5.2% of cases and was associated with less-severe illness. Our findings are consistent with the hypothesis that in less-developed areas, Cryptosporidium is a major pathogen, not only in acute but also in chronic childhood diarrhea, and may play an important role in the interaction between diarrhea and malnutrition.
Body Weight↗
Neutral lipid transfer protein does not regulate alpha-tocopherol transfer between human plasma lipoproteins.
Vitamin E has no known plasma carrier protein and is transported by plasma lipoproteins. The site of association of vitamin E in the lipoprotein particle and the mode of transfer of vitamin E between plasma lipoproteins have not been ascertained. Since neutral lipids (triglycerides and cholesterol esters) exchange between plasma lipoproteins by processes mediated by neutral lipid transfer protein, we questioned that if vitamin E, a hydrophobic molecule, is carried in the core of the lipoprotein particle then its transfer between plasma lipoproteins may be mediated by neutral lipid transfer protein. Transfer of D-alpha(5-methyl-3H)tocopherol from in vitro-labeled human plasma lipoprotein fractions to other plasma lipoproteins was measured under incubation conditions that were designed to yield markedly differing degrees of neutral lipid exchange. Despite the presence of the d greater than 1.21 g/ml lipoprotein-poor plasma fraction or purified lipid transfer protein that resulted in up to a 10-fold increase in neutral lipid transfer, vitamin E transfer between very low density lipoproteins, low density and high density lipoproteins remained constant. Even excess amounts of lipid transfer protein, which caused triglyceride transfer between very low density and high density lipoproteins to reach saturation, failed to affect significantly vitamin E transfer. Vitamin E distribution between lipoprotein fractions did correlated with lipoprotein mass ratios. Vitamin E transfer was higher as the protein ratio of acceptor lipoproteins to donor lipoproteins increased.(ABSTRACT TRUNCATED AT 250 WORDS)
Carrier Proteins↗
Asymptomatic cryptosporidiosis in a New York City day care center.
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Adult↗