Vitamin A and vitamin E replacement in abetalipoproteinemia.
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Abetalipoproteinemia↗
Biomedical subjects
L A Zech
Publications and source records attributed to L A Zech.
Apolipoprotein E metabolism in normolipoproteinemic human subjects.
Human apolipoprotein E (apoE) is a constituent of plasma very low density and high density lipoproteins and is important in modulating the catabolism of remnants of triglyceride-rich lipoproteins. There are three common isoforms of apoE, designated apoE-2, E-3, and E-4, which are coded by three separate alleles (epsilon 2, epsilon 3, and epsilon 4) at a single genetic locus and inherited in the population in a co-dominant fashion. ApoE-3 is the predominant apoE isoform in the normolipidemic population, and epsilon 3 has been proposed to be the normal allele. ApoE-3 metabolism was studied in nine normolipidemic subjects homozygous for the epsilon 3 allele. In these subjects, the plasma apoE-3 concentration was 4.8 +/- 1.2 mg/dl (mean +/- SD), the plasma apoE-3 residence time was 0.73 +/- 0.18 days, and the plasma apoE-3 production rate was 3.4 +/- 1.5 mg/kg-day. The apoE in males, when compared to females, tended to have a shorter residence time (0.63 +/- 0.15 days versus 0.83 +/- 0.16), a higher production rate (4.20 +/- 1.73 mg/kg-days versus 2.60 +/- 0.78), but a similar plasma concentration (5.1 +/- 1.5 mg/dl versus 4.5 +/- 0.8). ApoE-3 had a more rapid catabolism from plasma than other apolipoproteins previously studied (apolipoproteins A-I, A-II, A-IV, B-100, C-II, and C-III) except for apolipoprotein B-48. The catabolism of apoE-3 in the individual lipoprotein subfractions was also examined and apoE was shown to be catabolized most rapidly from the VLDL and slowest from the HDL. The results of the kinetic analysis of apoE metabolism are consistent with apoE being important in the catabolism of triglyceride-rich lipoproteins and with HDL serving as a reservoir for apoE to reassociate with newly secreted triglyceride-rich lipoproteins.
Adult↗
Apolipoprotein E alleles in severe hypertriglyceridaemia.
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Alleles↗
Massive omental reticuloendothelial cell lipid uptake in Tangier disease after splenectomy.
Tangier disease is a rare, autosomal recessive condition characterized by cholesterol ester deposition in reticuloendothelial cells, abnormal chylomicron remnants, decreased low-density lipoprotein levels, and a marked deficiency of high-density lipoproteins. Apolipoprotein A-I, a major protein constituent of chylomicrons and high-density lipoproteins, has been shown to be structurally and metabolically abnormal in this disease (apolipoprotein A-ITangier). A 63-year-old Tangier homozygous man is described, who underwent splenectomy because of thrombocytopenia and splenomegaly. Subsequently, a large orange mass developed at the base of the mesentery, with several smaller omental masses and thickening of the entire omentum due to infiltration with lipid-laden macrophages. Splenectomy appears to predispose to such deposition, since such masses have not been observed in other Tangier homozygotes. The spleen appears to play a significant role in the removal of abnormal lipoproteins in Tangier homozygotes; therefore, splenectomy may be contraindicated in Tangier disease.
Apolipoproteins↗
The effects of estrogen administration on plasma lipoprotein metabolism in premenopausal females.
The effects of estrogen administration (ethinyl estradiol; 0.1 mg, orally, daily) on plasma lipoprotein metabolism were investigated in five normolipidemic premenopausal females. Estrogen administration resulted in significant (P less than 0.05) mean increases in plasma cholesterol, triglyceride, very low density lipoprotein (VLDL)-cholesterol, and high density lipoprotein (HDL)-cholesterol of 18.8%, 87.0%, 123.1%, and 38.3%, respectively. Analytical ultracentrifugation demonstrated that HDL increases occurred mainly in the HDL2b subfraction (150.0% increase). Lipoprotein compositional analysis showed that estrogen administration caused significant increases in all VLDL and HDL constituents (protein, cholesterol, phospholipid, and triglyceride) as well as VLDL apolipoprotein (apo) B (118.9% increase) and HDL apoA-I (27.4% increase). No significant changes in LDL constituents were noted. Measurement of lipoprotein lipase and hepatic lipase enzymic activity in post-heparin plasma revealed no major change in lipoprotein lipase activity, but showed a significant decrease (43.8%) in hepatic lipase activity during estrogen administration. Radioiodinated VLDL and HDL kinetic data indicated increased VLDL apoB (86.1% rise) and HDL apoA-I (24.9% rise) synthesis during estrogen administration. These data are consistent with the concept that estrogen administration at the dose level studied in premenopausal females causes significant elevations in VLDL and HDL constituents, associated with enhanced production of VLDL apoB and HDL apoA-I.
Adult↗
NIH conference. Type III hyperlipoproteinemia: diagnosis, molecular defects, pathology, and treatment.
Type III hyperlipoproteinemia is characterized by increased plasma levels of triglycerides and cholesterol, palmar-tuberoeruptive xanthoma, and premature cardiovascular disease. Three major classes of molecular defects will predispose patients to develop type III hyperlipoproteinemia: a deficiency in apolipoprotein E, a structural defect in the E apolipoprotein, and a functional defect in the liver receptor system. Most patients with type III hyperlipoproteinemia have a structural defect in apolipoprotein E associated with increased synthesis and decreased catabolism of apolipoprotein E, delayed catabolism of chylomicron remnants, and development of plasma lipoprotein abnormalities characteristic of type III hyperlipoproteinemia. Analysis of cardiovascular disease in patients with type III hyperlipoproteinemia showed extensive coronary and peripheral vascular atherosclerosis indistinguishable from the atherosclerosis of non-hyperlipidemic and other dyslipoproteinemic patients. The xanthoma and elevated plasma cholesterol and triglyceride levels in patients with type III hyperlipoproteinemia respond to dietary and drug therapy.
Adolescent↗
Changes in plasma cholesterol and triglyceride levels after treatment with oral isotretinoin. A prospective study.
Twenty men with nodulocystic acne were treated with oral isotretinoin (13-cis-retinoic acid) for four months. Plasma lipids and lipoprotein determinations were obtained before and during treatment to quantitate the effects of oral isotretinoin on lipid metabolism. Maximum isotretinoin-induced elevations in plasma triglyceride and cholesterol levels were 67% and 16%, respectively. Additional maximal changes included very-low-density lipoprotein cholesterol increases of 56%, low-density lipoprotein cholesterol increases of 22%, and high-density lipoprotein decreases of 10% from pretreatment values. Chronic increases in plasma cholesterol levels, increases in low-density lipoprotein cholesterol levels, and decreases in high-density lipoprotein cholesterol levels may predispose subjects to premature atherosclerosis. Because of the potential for unmasking an occult lipid or lipoprotein disorder, the plasma lipid and lipoprotein profiles of subjects receiving isotretinoin should be carefully monitored.
Acne Vulgaris↗
Metabolism of human apolipoproteins A-I and A-II: compartmental models.
The metabolism of radioiodinated apolipoproteins (apo) A-I and A-II have been examined using the techniques of compartmental modeling. The model for apoA-I contains two plasma compartments decaying at different rates. One component of apoA-I has a residence time of 3.8 days and the second has a residence time of 6.1 days. In contrast, the apoA-II model has only one plasma component, with a residence time of 5.5 days, which decays through two distinct pathways. Twenty-seven percent of apoA-II decays through a pathway that takes 1.1 days longer to reach the urine than the remaining 73% which decays through the more direct path. These differences in the metabolism exist in both male and female populations. Comparison of fasting and nonfasting concentrations of apoA-I revealed that apoA-I concentration was elevated 0.5 standard deviations in the nonfasting samples while there was no significant difference in the apoA-II concentrations. The fasting apoA-I concentrations were found to be less stable over the study period when compared to fasting apoA-II concentrations. These findings are interpreted as indicating that apoA-I and apoA-II each have a separate metabolism which overlaps when they are present on the same lipoprotein particle. Furthermore, these findings are consistent with the concept that apoA-I metabolism is influenced more by perturbations such as dietary modulation.
Adult↗
Phenotype study of apolipoprotein E isoforms in hyperlipoproteinaemic patients.
It has been suggested that apolipoprotein E (apoE) is inherited at a single genetic locus with three common alleles designated E2, E3, and E4. The products of these three alleles are apoE2, apoE3, and apoE4. The apoE phenotypes of 74 normal subjects and 226 hyperlipoproteinaemic subjects were ascertained by gel isoelectrofocusing. Patients with type I, type IIa, type IIb, and type IV hyperlipoproteinaemia had an apoE phenotypic distribution which was similar to that of normal subjects, with 40.0 to 60.0% being homozygous for E3. In contrast, 75% of type III patients had an E2 phenotype and 25% were E2/3 heterozygotes. Among type V patients 31.4% had an E4 phenotype, and 42.9% were E4 heterozygotes. No type III patient and only 5.7% of type V patients had E3 phenotype. The results suggest that apoE2 and apoE4 are associated with two distinctly different dyslipoproteinaemias and that apoE has at least two different physiological functions.
Apolipoproteins↗
Increased prevalence of apolipoprotein E4 in type V hyperlipoproteinemia.
Type V hyperlipoproteinemia (HLP) is characterized clinically by hepatosplenomegaly, occasional eruptive xanthomas, and an increased incidence of pancreatitis. These patients have striking hypertriglyceridemia due to increased plasma chylomicron and very low density lipoprotein concentrations in the fasting state, without a deficiency of lipoprotein lipase or its activator protein, apolipoprotein (apo) C-II. ApoE, a protein constituent of triglyceride-rich lipoproteins, has been implicated in the receptor-mediated hepatic uptake of these particles. ApoE has three major alleles: E2, E3, and E4, and the products of these alleles are apoE2, apoE3, and apoE4, respectively. ApoE phenotypes were determined in 30 type V HLP patients as well as in 37 normal volunteers. Among the type V patients, 33.3% were noted to be homozygous, and 40.0% heterozygous for E4 (normal, 2.7 and 21.6%, respectively). These data suggest that apoE4 may play a role in the etiology of the hyperlipidemia in a significant number of type V HLP patients.
Apolipoprotein E4↗
Tangier disease. High density lipoprotein deficiency due to defective metabolism of an abnormal apolipoprotein A-i (ApoA-ITangier).
Tangier disease is a rare familial disorder characterized by enlarged orange tonsils, transient peripheral neuropathy, hepatosplenomegaly, and lymphadenopathy, as well as striking reductions in plasma high density lipoproteins (HDL) and their major protein constituents, apolipoproteins (apo)A-I and A-II. In order to test the hypothesis that Tangier patients have abnormal apoA-I or apoA-II, the in vitro lipoprotein binding and in vivo metabolic characteristics of these proteins isolated from normal and Tangier plasma, were studied in normal subjects and patients with Tangier disease. After incubation with normal plasma, significantly greater percentages of radiolabeled Tangier apoA-I were associated with the 1.063-g/ml supernate (6%) and the 1.21 g/ml infranate (19%), and a lower percentage with HDL (75%), than those observed for normal apoA-I (2, 8, and 90%, respectively). In contrast, the lipoprotein binding properties of normal and Tangier apoA-II were very similar. Following the injection of radiolabeled normal and Tangier apoA-I into normal subjects (n = 4), the mean residence times of the specific activity for apoA-I(Tangier) were significantly lower, both in plasma (1.29 d) and in HDL (1.34 d), than those observed for normal apoA-I (3.80 and 4.06 d). In Tangier homozygotes the decay rates of these tracers were very rapid and were similar. No significant differences between the kinetics of normal and Tangier apoA-II were observed in normal subjects (n = 2). Tangier homozygotes (n = 3) had mean plasma HDL cholesterol, apoA-I, and apoA-II concentrations that were 4, 2, and 11% of normal (n = 24), respectively, whereas for heterozygotes (n = 3) these values were 46, 62, and 68% of normal. In homozygotes, in contrast to normals or heterozygotes, a significant fraction of both apoA-I and apoA-II were found in the 1.063-g/ml supernate instead of in HDL. Homozygotes had apoA-I(Tangier) synthesis rates and residence times that were 41 and 5% of values observed for normal apoA-I in normal subjects, and for apoA-II in homozygotes, these parameters were 63 and 18% of normal. Heterozygotes had apoA-I synthesis rates and residence times that were 92 and 66% of normal, and for apoA-II these values were 101 and 64% of normal. These data are consistent with the concept that apoA-I(Tangier) is functionally and metabolically distinct from normal apoA-I, and is the cause of the striking hypercatabolism of apoA-I and apoA-II, and the lipoprotein abnormalities observed in Tangier disease.
Adult↗
Human apolipoprotein A-I and A-II metabolism.
The kinetics of the major apolipoproteins (apo) of plasma high density lipoproteins (HDL), apoA-I and apoA-II, were examined in a total of 44 individual tracer studies in 22 normal male and female subjects. Following the intravenous injection of radioiodinated HDL, the specific radioactivity decay of apoA-I within HDL (residence time, 5.07 +/- 1.53 days), as determined by column chromatography, was significantly (P < 0.01) faster than that of apoA-II (residence time, 5.96 +/- 1.84 days). The specific radioactivity decay of apoA-I within HDL when labeled on HDL or as apoA-I was found to be almost identical. Similar results were obtained for apoA-II. Analysis of simultaneous paired radiolabeled apoA-I and apoA-II studies revealed that the mean apoA-I plasma residence time (4.46 +/- 1.04 days) was significantly (P < 0.01) shorter than that for apoA-II (4.97 +/- 1.06 days). Females had significantly (P < 0.01) higher apoA-I plasma concentrations (124 +/- 24 mg/dl) and apoA-I synthesis rates (13.58 +/- 2.23 mg/kg. day) than did males (108 +/- 16 mg/dl, and 11.12 +/- 1.92 mg/kg. day, respectively). Plasma apoA-I levels were correlated with plasma apoA-I residence times, but not synthesis rates; and apoA-II concentrations were correlated only with apoA-II whole body residence times. ApoA-I and apoA-II plasma residence times were inversely correlated with plasma triglyceride levels. These data are consistent with the following concepts: 1) labeling of apoA-I and apoA-II as apolipoproteins or on HDL does not affect their specific radioactivity decay within HDL; 2) the mean residence time of apoA-I both in plasma and in HDL is significantly shorter than that of apoA-II; 3) the increased apoA-I levels seen in female subjects are due to increased apoA-I synthesis; and 4) the plasma apoA-I residence time, which is inversely correlated with plasma triglyceride levels, is an important determinant of apoA-I concentration in both males and females.-Schaefer, E. J., L. A. Zech, L. L. Jenkins, T. J. Bronzert, E. A. Rubalcaba, F. T. Lindgren, R. L. Aamodt, and H. B. Brewer, Jr. Human apolipoprotein A-I and A-II metabolism.
Adult↗
Type III hyperlipoproteinemia: defective metabolism of an abnormal apolipoprotein E.
The apolipoprotein E isolated from plasma of individuals with type III hyperlipoproteinemia (HLP) shows an abnormal pattern when it is examined by isoelectric focusing. Compared to apolipoprotein E from normal subjects, apolipoprotein E isolated from subjects with type III HLP had a decreased fractional catabolic rate in vivo in both type III HLP patients and normal individuals. The delayed catabolism of apolipoprotein E in type III HLP patients may be responsible for the lipid and lipoprotein abnormalities characteristic of these patients.
Apolipoproteins↗
Transport of apolipoproteins A-I and A-II by human thoracic duct lymph.
The daily transport of human plasma apolipoproteins A-I and A-II, triglyceride, and total cholesterol from the thoracic duct lymph into plasma was measured in two subjects before and three subjects after renal transplantation. Lymph triglyceride transport was approximately 83% of the daily ingested fat loads, whereas lymph cholesterol transport was consistently greater than the amount of daily ingested cholesterol. Lymph apolipoprotein transport significantly (P < 0.05) exceeded the predicted apolipoprotein synthesis rate by an average of 659+/-578 mg/d for apolipoprotein A-I and 109+/-59 mg/d for apolipoprotein A-II among the five subjects. It is estimated that 22-77% (apolipoprotein A-I) and 28-82% (apolipoprotein A-II) of daily total body apolipoprotein synthesis takes place in the intestine. Lymph high density lipoprotein particles are mostly high density lipoprotein(2b) and high density lipoprotein(2a) and have a greater overall relative triglyceride content and a smaller relative cholesteryl ester content when compared with homologous plasma high density lipoproteins. The major quantity of both lymph apolipoprotein A-I (81+/-8%) and apolipoprotein A-II (90+/-11%) was found within high density lipoproteins with almost all of the remainder found in chylomicrons and very low density lipoproteins. The combined results are consistent with a major contribution of the intestine to total body synthesis of apolipoprotein A-I and apolipoprotein A-II. An important role of lymph in returning filtered apolipoprotein to plasma in association with high density lipoproteins is proposed. Accompanying the return of filtered apolipoprotein to the plasma is a probable transformation, both in size and composition, of at least some of the lymph high density lipoprotein(2b) and high density lipoprotein(2a) particles into high density lipoprotein(3).
Apolipoproteins↗
Metabolism of high density lipoprotein subfractions and constituents in Tangier disease following the infusion of high density lipoproteins.
The metabolism of apolipoproteins A-I and A-II, as well as other high density lipoprotein (HDL) constituents, was studied in patients with homozygous familial HDL deficiency (Tangier disease) prior to and after plasma exchange or HDL infusion. Mean plasma apoA-I, apoA-II, and HDL cholesterol values in homozygotes (n = 2) were 2.0 mg/dl, 2.7 mg/dl, and 1.5 mg/dl, respectively, and in a normal control subject were 125.1 mg/dl, 23.0 mg/dl, and 53.0 mg/dl, respectively. Based on radioiodinated apoA-I and apoA-II kinetic studies in the baseline state, synthesis rates for apoA-I and apoA-II in mg/kg/day were 3.81 and 1.61, respectively, in one homozygote (patient B) and 11.82 and 1.99, respectively, in the normal subject. ApoA-I and apoA-II plasma residence times in days were 0.22 and 0.81, respectively, in the homozygote, and 4.04 and 4.44, respectively, in the normal subject. These data indicate that this homozygote had both a moderate decrease in the synthetic rates of apoA-I and apoA-II, as well as a marked decrease in the plasma residence times of these two apolipoproteins. In one homozygote (patient A) following a complete plasma exchange during cardiopulmonary bypass, plasma HDL cholesterol, apoA-I, and apoA-II levels were very similar to pre-exchange values within 64 hr after exchange. A second homozygote (patient B) received HDL intravenously as well as 125I-labeled apoA-I and 131I-labeled apoA-II. Following infusion, the residence time in days for HDL subfractions, HDL2b, HDL2a, and HDL3 were 0.1, 0.8, and 2.7, respectively. HDL protein and phospholipid both had a monoexponential decay, with residence times of 0.7 days, while HDL triglyceride disappeared monoexponentially with a residence time of 0.5 days. HDL cholesterol had a biexponential decay, with the residence time of the slow component being 0.7 days. Plasma and HDL apoA-I decayed down to baseline values significantly faster than did plasma and HDL apoA-II. ApoA-II specific radioactivity decreased throughout the course of the infusion study in both plasma and HDL, while apoA-I specific radioactivity decreased slightly, then rose, and subsequently declined in both plasma and HDL. The data indicate that the rapid and altered catabolism of apoA-I and apoA-II in Tangier homozygotes persists despite major increases in the plasma pool size of these proteins. In addition, following HDL infusion, HDL2b and HDL2a disappeared at a faster rate than HDL3, HDL cholesterol and triglyceride were catabolized at a faster rate than HDL protein and phospholipid, and apoA-I disappeared more rapidly than apoA-II. These observations may have important implications with regard to the catabolism of HDL subfractions and constituents in normal man.
Adult↗
Coronary heart disease prevalence and other clinical features in familial high-density lipoprotein deficiency (Tangier disease).
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Adolescent↗
The metabolism of apolipoprotein B in subjects with hypertriglyceridemia and polydisperse LDL.
This research concerns the metabolism of apolipoprotein B (apoB) in hypertriglyceridemic subjects with polydisperse or heterogeneous LDL. Five subjects maintained under constant dietary control had blood samples fractionated into very low density lipoprotein (VLDL), Sf 20, Sf 10, and Sf 4 LDL, and plasma free leucine, and in three subjects VLDL was further fractionated by size. Apo B was isolated, and the masses of the plasma apo B pools were measured for these lipoproteins. Following injection of [3H]leucine as a metabolic tracer the specific activity of apo B in these lipoproteins and of plasma leucine were measured over 7 or 14 days. The kinetic data were examined using multicompartmental analysis and interpreted in terms of our previous model of apo B metabolism (1975. Federation Proc. 24: 2263.). Newly synthesized apo B, secreted as large VLDL, is metabolized by a delipidation chain yielding intermediate density lipoprotein (IDL), consisting of small VLDL and Sf 20 LDL, and eventually forms small, Sf4 LDL. LDL is metabolized in a steplike process from Sf 20 to Sf 10 and Sf 4 LDL. A second major biosynthetic input in apo B enters directly into IDL and 1/4 to 2/3 of newly synthesized apo B enters plasma by this route. Total apo B synthesis in these subjects is 5- to 10-fold greater than reported for normals. The rate of transport of VLDL apo B and IDL is slower than normal with a residence time which is increased about twofold; however, the VLDL apo B pool is enlarged 5- to 10-fold, and thus the quantity of apo B entering and leaving this pool per hour is much greater than in the normal. Two major pathways for apo B catabolism occur. Between 1/3 and 2/3 of apo B is metabolized through LDL, disappearing from plasma as Sf 4 LDL. The remainder of apo B disappears from plasma IDL directly. The four major findings in this kinetic study of apo B metabolism in hypertriglyceridemic subjects with polydisperse LDL are: 1) The marking increase in apo B synthesis; 2) the biosynthetic input of much of this apo B directly into IDL; 3) the large catabolic pathway of apo B which leaves IDL, and 4) the stepwise metabolism of LDL by which Sf 20, Sf 10 and Sf 4 LDL are generated.
Adult↗
Kinetic model for production and metabolism of very low density lipoprotein triglycerides. Evidence for a slow production pathway and results for normolipidemic subjects.
A model for the synthesis and degradation of very low density lipoprotein triglyceride (VLDL-TG) in man is proposed to explain plasma VLDL-TG radioactivity data from studies conducted over a 48-h interval after injection of glycerol labeled with 14C, 3H, or both. The curve describing the radioactivity of plasma VLDL triglycerides reaches a maximum at about 2 h, after which the decay is biphasic in all cases; the late curvature becoming evident only after 8--12 h. To fit the complex curve, it was necessary to postulate two pathways for the incorporation of plasma glycerol into VLDL-TG, one much slower than the other. A process of stepwise delipidation of VLDL in the plasma compartment, previously proposed for VLDL apoprotein models, was also necessary. Predicted VLDL-TG synthesis rates calculated with this model can differ significantly from those based on experiments of shorter duration in which the slow VLDL-TG component is not apparent. The results of these studies strongly support the interpretation that the late, slow component of the VLDL-TG activity curve is predominantly due to the slowly turning-over precursor compartment in the conversion pathway and is not due either to a slow compartment in the labeled precursor, plasma free glycerol, or to an exchange of plasma VLDL-TG with an extravascular compartment. It also cannot, in these studies, be attributed to a slowly turning-over VLDL-TG moiety in the plasma. The model was tested with data from 59 studies including normal subjects and patients with obesity and(or) various forms of hyperlipoproteinemia. Good fits were obtained in all cases, and the estimated parameter values and their uncertainties for 13 normolipemic nonobese subjects are presented. Sensitivty testing was carried out to determine how critical various parameter estimations are to the assumptions introduced in the modeling.
Glycerol↗