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Apolipoprotein B metabolism in subjects with deficiency of apolipoproteins CIII and AI. Evidence that apolipoprotein CIII inhibits catabolism of triglyceride-rich lipoproteins by lipoprotein lipase in vivo [Case Report]

Ginsberg, H N; Le, N A; Goldberg, I J; Gibson, J C; Rubinstein, A; Wang-Iverson, P; Norum, R; Brown, W V
Previous data suggest that apolipoprotein (apo) CIII may inhibit both triglyceride hydrolysis by lipoprotein lipase (LPL) and apo E-mediated uptake of triglyceride-rich lipoproteins by the liver. We studied apo B metabolism in very low density (VLDL), intermediate density (IDL), and low density lipoproteins (LDL) in two sisters with apo CIII-apo AI deficiency. The subjects had reduced levels of VLDL triglyceride, normal LDL cholesterol, and near absence of high density lipoprotein (HDL) cholesterol. Compartmental analysis of the kinetics of apo B metabolism after injection of 125I-VLDL and 131I-LDL revealed fractional catabolic rates (FCR) for VLDL apo B that were six to seven times faster than normal. Simultaneous injection of [3H]glycerol demonstrated rapid catabolism of VLDL triglyceride. VLDL apo B was rapidly and efficiently converted to IDL and LDL. The FCR for LDL apo B was normal. In vitro experiments indicated that, although sera from the apo CIII-apo-AI deficient patients were able to normally activate purified LPL, increasing volumes of these sera did not result in the progressive inhibition of LPL activity demonstrable with normal sera. Addition of purified apo CIII to the deficient sera resulted in 20-50% reductions in maximal LPL activity compared with levels of activity attained with the same volumes of the native, deficient sera. These in vitro studies, together with the in vivo results, indicate that in normal subjects apo CIII can inhibit the catabolism of triglyceride-rich lipoproteins by lipoprotein lipase.
PMCID:423815
PMID: 3095375
ISSN: 0021-9738
CID: 952532

Production and use of an inhibitory monoclonal antibody to human lipoprotein lipase

Goldberg, I J; Paterniti, J R Jr; France, D S; Martinelli, G; Cornicelli, J A
Studies were performed to produce a monoclonal antibody to human lipoprotein lipase, verify the specificity of the antibody for lipoprotein lipase, and use this antibody for detection of lipoprotein lipase protein in human post-heparin plasma. Partially purified lipoprotein lipase from human milk was used as an antigen for the production of anti-lipoprotein lipase antibodies in mice. The spleen was removed from the animal having the highest titer of inhibitory antibodies to lipoprotein lipase and the cells were fused mouse myeloma cells. Culture media from the resulting hybridomas were screened for their ability to inhibit lipoprotein lipase catalytic activity. This screening procedure thus identified only those hybridomas which produced antibodies directed against lipoprotein lipase. One monoclonal antibody, from one clone, was selected for detailed study. The specificity of this antibody for lipoprotein lipase protein was established by three methods. First, post-heparin plasma lipoprotein lipase activity and immunoreactivity detected by an enzyme-linked immunosorbent assay (ELISA) co-eluted during heparin-agarose and phenyl-Sepharose chromatography. Second, the antibody detected a protein which was released into the circulation after intravenous injection of heparin into humans. Third, both immunoreactive lipoprotein lipase protein and lipoprotein lipase enzymatic activity were lost by heat-inactivation of lipoprotein lipase. The use of active enzyme as an antigen and the procedure used to screen the monoclonal antibody-producing hybridomas allowed the production of an inhibitory anti-human lipoprotein lipase monoclonal antibody. This antibody is useful for detection of lipoprotein lipase protein in plasma and should allow for immunohistochemical staining of active lipoprotein lipase enzyme in tissues. Moreover, the methods described for screening hybridomas may be modified and used to produce specific antibodies against other partially purified enzymes.
PMID: 3756191
ISSN: 0006-3002
CID: 952642

Plasma lipoprotein abnormalities associated with acquired hepatic triglyceride lipase deficiency [Case Report]

Goldberg, I J; Mazlen, R G; Rubenstein, A; Gibson, J C; Paterniti, J R Jr; Lindgren, F T; Brown, W V
Two enzymes, lipoprotein lipase (LPL) and hepatic triglyceride lipase (HTGL), are released into human plasma after intravenous injection of heparin. LPL is the major enzyme responsible for initiating catabolism of chylomicrons and very-low-density lipoproteins (VLDL). The physiological role of HTGL is less certain. HTGL has been postulated to be an alternate enzyme to LPL in hydrolysis of triglyceride in VLDL and to be an important enzyme for removal of phospholipid from both low-density lipoproteins (LDL) and high-density lipoproteins (HDL). In this latter role, this enzyme would convert larger, lighter lipoprotein particles to smaller denser particles. HTGL deficiency has been found in severe liver disease and with a genetic deficiency of this enzyme. A unique patient is described with acquired hepatic triglyceride lipase deficiency and vitamin A intoxication. This patient developed hypercholesterolemia with an increase in both LDL and HDL. An increased proportion of lighter LDL (LDL1) and HDL (HDL2) was noted. In addition, after administration of heparin there was no shift in the distribution of apoE in plasma fractionated using a column containing 4% agarose. These findings are consistent with a postulated role of HTGL in metabolism of light LDL and HDL particles and some classes of apoE containing lipoproteins.
PMID: 4033424
ISSN: 0026-0495
CID: 952542

Immunoaffinity isolation of apolipoprotein E-containing lipoproteins

Gibson, J C; Rubinstein, A; Ngai, N; Ginsberg, H N; Le, N A; Gordon, R E; Goldberg, I J; Brown, W V
Discrete apolipoprotein E-containing lipoproteins can be identified when EDTA plasma is fractionated on columns of 4% agarose. The present study has demonstrated, by physical and metabolic criteria, that these apolipoprotein E-containing lipoprotein subclasses may be further isolated by immunoaffinity chromatography. Whole plasma was first bound to an anti-apolipoprotein E immunoadsorbent prior to gel filtration on 4% agarose. After elution from the affinity column and dialysis, the bound fraction was chromatographed on 4% agarose. Discrete subfractions of apolipoprotein E could be demonstrated within elution volumes similar to those observed in the original plasma. When whole plasma was first submitted to gel filtration and the apolipoprotein E-containing lipoproteins of either intermediate- or of high-density lipoprotein (HDL) size were subsequently bound to anti-apolipoprotein E columns, the bound eluted fractions maintained their size and physical properties as shown by electron microscopy and by rechromatography on columns of 4% agarose. The metabolic integrity of apolipoprotein E-containing very-low-density lipoproteins (VLDL) was examined by coinjection into a cynomolgus monkey of 125I-labeled apolipoprotein E-rich and 131I-labeled apolipoprotein E-deficient human VLDL which had been separated by immunoaffinity chromatography. The plasma specific activity time curves of the apolipoprotein B in VLDL, intermediate-density (IDL) and low-density (LDL) lipoproteins demonstrated rates of decay and precursor-product relationships similar to those obtained after injection of whole labeled VLDL, supporting the metabolic integrity of VLDL isolated by immunoaffinity chromatography.
PMID: 3924105
ISSN: 0006-3002
CID: 952552

Treatment of common lipoprotein disorders

Brown, W V; Goldberg, I J; Ginsberg, H N
The pathogenesis of arteriosclerosis is not yet fully understood. The growing body of scientific information strongly indicates that the plasma lipoproteins are playing a crucial role in the development of this disease. We now have conclusive information that dietary cholesterol can produce arteriosclerosis in animals and its removal from the diet can result in regression of these lesions. Most importantly, we know that reducing plasma cholesterol in humans will prevent mortality and morbidity related to the clinical sequelae of arteriosclerosis. A diet can be prescribed that can produce profound reductions in lipoprotein levels in many individuals. The rate of success in achieving modifications that reduce plasma cholesterol is very high. Most patients over time find a diet with reduced cholesterol and saturated fat to be quite palatable. As food suppliers become more active in emphasizing low fat, low cholesterol products, and as restaurants see a demand for healthier entrees, the task for the physician and nutritionist will become much easier. Achieving sustained weight reduction is a much more difficult problem, but this too can be accomplished in many patients if the health professionals maintain a hopeful supportive approach. Ultimately, it is the patient's responsibility to bring about these lifestyle changes. It is the physician's and nutritionist's job to monitor the process and provide sound information and encouragement. For individuals with severe lipoprotein disorders such as familial hypercholesterolemia where diet therapy is helpful but not adequate, the use of medications is now indicated (bile acid binding resins and nicotinic acid). Other medications that promise additional effectiveness and safety are under development (Compactin, Mevinolin). It is our belief that control of coronary heart disease and stroke requires appropriate treatment of lipoprotein disorders and the methods for a strong beginning in this endeavor are at hand.
PMID: 6330792
ISSN: 0033-0620
CID: 952562

Measurement of heparin-releasable triacylglycerol lipases

Gibson, J C; Paterniti, J R Jr; Goldberg, I J
PMID: 6390053
ISSN: 0160-8584
CID: 952652

Measurement of lipoprotein lipase and hepatic triacylglycerol lipase in post-heparin plasma of the cynomolgus monkey

Goldberg, I J; Paterniti, J R Jr; Brown, W V
Conditions for measurement of the lipolytic activities, lipoprotein lipase and hepatic triacylglycerol lipase in cynomolgus monkey postheparin plasma are described. The two activities are separable by heparin-Sepharose chromatography. Goat anti-human hepatic triacylglycerol lipase serum inhibits monkey hepatic triacylglycerol lipase activity and allows direct measurement of lipoprotein lipase in post-heparin plasma. While both human and homologous serum can be used as a source of activator apolipoprotein, homologous serum produces a much greater activation.
PMID: 6849965
ISSN: 0006-3002
CID: 952572

Increased catabolism of native and cyclohexanedione-modified low density lipoprotein in subjects with myeloproliferative diseases

Ginsberg, H; Goldberg, I J; Wang-Iverson, P; Gitler, E; Le, N A; Gilbert, H S; Brown, W V
We previously demonstrated reduced levels of low density lipoprotein (LDL) cholesterol in association with increased total fractional catabolic rates (FCR( of LDL apoprotein B (apo B) in individuals with myeloproliferative diseases (MPD). The removal of LDL from plasma and interstitial fluid is mediated via receptor and nonreceptor pathways. We attempted to quantitate LDL catabolism via each of these pathways in subjects with MPD and control subjects. The total FCR of LDL apo B was measured using radiolabeled native LDL. The FCR of radiolabeled cyclohexanedione-modified LDL (CHD-LDL) was used to assess the nonreceptor-mediated catabolism of LDL. Total FCR (mean +/- SD) was elevated in MPD vs controls (0.78 +/- 0.32 vs 0.45 +/- 0.11, p less than 0.01). CHD-LDL FCR was also increased in MPD vs controls (0.62 +/- 0.53 vs 0.23 +/- 0.04, p less than 0.01). Studies of the plasma decay of radiolabeled native and CHD-LDL preparations after their injection into cynomolgus monkeys indicated that CHD-LDL preparations from MPD and controls were removed at the same rates in those primates and that all CHD-LDL preparations were catabolized more slowly than the native LDL preparations. Studies in vitro indicated that CHD modification of LDL significantly reduced the rate of degradation of this lipoprotein by a specific high-affinity receptor pathway in normal human monocyte-derived macrophages and cultured human fibroblasts. We conclude that the catabolism of both native and CHD-LDL apo B is increased in subjects with MPD. If CHD-LDL is a valid tracer of nonreceptor-mediated removal of native LDL in individuals with MPD, our results indicate that the reduced LDL cholesterol concentrations demonstrated in these subjects are associated with increased nonreceptor-mediated catabolism of LDL apo B. At this time, both neoplastic cells and activated monocyte-macrophages appear to be likely sites of these abnormalities.
PMID: 6847522
ISSN: 0276-5047
CID: 952582

Transportal blood sampling for preoperative localization of insulinomas

Rayfield, E J; Goldberg, I J; Giegerich, E W; Mitty, H A; Aufses, A Jr
PMID: 6312299
ISSN: 0027-2507
CID: 952612

Differential immunoreactivity of plasma glucagon components in man: studies with different glucagon antibodies

Soybel, D; Jaspan, J; Polonsky, K; Goldberg, I; Rayfield, E; Tager, H
To evaluate the relationship between glucagon antibody antigenic determinants and selective reactivity with plasma void volume (Vo) and lower molecular weight immunoreactive glucagon (IRG) components, we studied plasma IRG levels and molecular profiles in normal subjects and patients with disturbances in plasma glucagon levels using three glucagon antibodies, 30K and P7 raised against the whole peptide and antibody X4 raised against the C-terminal tryptic fragment of glucagon. In normal subjects and pancreatectomized patients, plasma IRG levels were 2- to 3-fold higher with the C-terminus-directed antibody X4 than with either 30K or P7, but in glucagonoma and uremic patients, this discrepancy was smaller. Gel filtration analysis revealed that these antibodies reacted identically with 3500 mol wt IRG and 9000 mol wt IRG in normal, glucagonoma, pancreatectomized, and uremic plasma. Relative immunoreactivity of Vo IRG was approximately 5:2:1 with antibodies X4, 30K, and P7, respectively. In two subjects with unexplained hyperglucagonemia, recovery of IRG was entirely in the Vo, with antiserum X4 reacting one third as well as 30K and P7 not reacting at all. Furthermore, this material did not dilute out in parallel to glucagon standard. These data indicate differential immunoreactivity of the high molecular weight circulating IRG component, with a series of three glucagon antibodies reacting similarly with all other plasma IRG fractions, and suggest that Vo IRG material in plasma is predominantly the result of an immunologically cross-reacting peptide sequence in a plasma protein. The selective immunoreactivity of this component with different antibodies has important implications for the glucagon RIA and may have some bearing on other immunoassays as well.
PMID: 6185527
ISSN: 0021-972x
CID: 952622