Development of an integrated model for analysis of the kinetics of apolipoprotein B in plasma very low density lipoproteins, intermediate density lipoproteins, and low density lipoproteins.

To quantify more precisely the metabolism of apolipoprotein B (apo B) in human beings, an integrated model was developed for the analysis of the isotope kinetics of apo B in very low density lipoproteins (VLDL), intermediate density lipoproteins (IDL), and low density lipoproteins (LDL). The experimental basis for model development was a series of 30 triple-isotope studies in which patients received autologous 131I-VLDL, 125I-IDL, and [3H]glycerol as a precursor of VLDL triglycerides. The currently proposed model contains the following components: (a) a VLDL delipidation cascade that has a variable number of subcompartments, (b) a slowly catabolized pool of VLDL, (c) an IDL compartment consisting of two closely connected subcompartments, one of which is outside the immediate circulation, and (d) a two-compartment subsystem for LDL. Because mass data indicate that not all VLDL were converted to LDL, the model allows for irreversible removal of apo B from VLDL (or IDL) subsystems. It accounts for apparent "direct" input of LDL by postulating an early, rapidly metabolized compartment of VLDL that is converted directly to IDL. The model appears to be consistent with specific activity curves from the current triple-isotope studies and with present concepts of lipoprotein physiology; it also can be used to quantify pathways of lipoprotein apo B transport in normal and abnormal states.

[1]  R. Phair,et al.  Preliminary model for human lipoprotein metabolism in hyperlipoproteinemia. , 1975, Federation proceedings.

[2]  S. Grundy,et al.  Kinetic model for production and metabolism of very low density lipoprotein triglycerides. Evidence for a slow production pathway and results for normolipidemic subjects. , 1979, The Journal of clinical investigation.

[3]  J. Marsh.  Apoproteins of the lipoproteins in a nonrecirculating perfusate of rat liver. , 1976, Journal of lipid research.

[4]  N. Nakaya,et al.  Synthesis and release of low density lipoproteins by the isolated perfused pig liver. , 1977, The Journal of biological chemistry.

[5]  M. Berman,et al.  1 – Kinetic Analysis and Modeling: Theory and Applications to Lipoproteins , 1982 .

[6]  S. Grundy,et al.  Isopropanol precipitation method for the determination of apolipoprotein B specific activity and plasma concentrations during metabolic studies of very low density lipoprotein and low density lipoprotein apolipoprotein B. , 1983, Journal of lipid research.

[7]  S. Grundy,et al.  Effects of Saturated and Polyunsaturated Fat Diets on the Chemical Composition and Metabolism of Low Density Lipoproteins in Man , 2022 .

[8]  W. Hazzard,et al.  Splanchnic metabolism of plasma apolipoprotein B: studies of artery-hepatic vein differences of mass and radiolabel in fasted human subjects. , 1981, The Journal of clinical investigation.

[9]  N. Fidge,et al.  Metabolic heterogeneity in the formation of low density lipoprotein from very low density lipoprotein in the rat: evidence for the independent production of a low density lipoprotein subfraction. , 1978, Journal of lipid research.

[10]  J. Kane,et al.  Heterogeneity of apolipoprotein B: isolation of a new species from human chylomicrons. , 1980, Proceedings of the National Academy of Sciences of the United States of America.

[11]  D. Illingworth.  Metabolism of lipoproteins in nonhuman primates. Studies on the origin of low density lipoprotein apoprotein in the plasma of the squirrel monkey. , 1975, Biochimica et biophysica acta.

[12]  G. Thompson,et al.  Low density lipoprotein turnover in familial hypercholesterolaemia after plasma exchange , 1976 .

[13]  B. Lewis,et al.  Conversion of very low density lipoprotein to low density lipoprotein. A metabolic study of apolipoprotein B kinetics in human subjects. , 1975, The Journal of clinical investigation.

[14]  S. Grundy,et al.  Influence of obesity on the metabolism of apolipoprotein B in humans. , 1985, The Journal of clinical investigation.

[15]  N. Nakaya,et al.  Synthesis of plasma lipoproteins by the isolated perfused liver from the fasted and fed pig. , 1977, The Journal of biological chemistry.

[16]  P. Nestel,et al.  Catabolism of very low density lipoprotein B apoprotein in man. , 1978, The Journal of clinical investigation.

[17]  B. Lewis,et al.  Quantitative studies of ver low densit lipoprotein: conversion to low densit lipoprotein in normal controls and primar hperlipidaemic states and the role of direct secretion of low densit lipoprotein in heterozgous familial hpercholesterolaemia , 1980, European journal of clinical investigation.

[18]  B. Lewis,et al.  Metabolism of Very Low Density Lipoproteins in Hyperlipidaemia: Studies of Apolipoprotein B Kinetics in Man , 1976, European journal of clinical investigation.

[19]  R. Havel,et al.  Characterization of human very low density lipoproteins containing two electrophoretic populations: double pre-beta lipoproteinemia and primary dysbetalipoproteinemia. , 1977, Journal of lipid research.

[20]  A. Sniderman,et al.  Low Density Lipoprotein: A METABOLIC PATHWAY FOR RETURN OF CHOLESTEROL TO THE SPLANCHNIC BED , 1978 .

[21]  R. Havel,et al.  Secretion of nascent lipoproteins and apolipoproteins by perfused livers of normal and cholesterol-fed guinea pigs. , 1982, Journal of lipid research.

[22]  S. Grundy,et al.  Chylomicron clearance in normal and hyperlipidemic man. , 1976, Metabolism: clinical and experimental.

[23]  M. Brown,et al.  Lipoprotein receptors in the liver. Control signals for plasma cholesterol traffic. , 1983, The Journal of clinical investigation.

[24]  R. Levy,et al.  The metabolism of low density lipoprotein in familial type II hyperlipoproteinemia. , 1972, The Journal of clinical investigation.

[25]  B. Lewis,et al.  Kinetic bases of the primar hperlipidaemias: studies of apolipoprotein B turnover in geneticall defined subjects , 1980 .

[26]  D. Bilheimer,et al.  On the metabolic conversion of human plasma very low density lipoprotein to low density lipoprotein. , 1973, Biochimica et biophysica acta.

[27]  S. Grundy,et al.  Comparisons of metabolism of apolipoprotein B in normal subjects, obese patients, and patients with coronary heart disease. , 1985, The Journal of clinical investigation.

[28]  K. Walton,et al.  The significance of alterations in serum lipids in thyroid dysfunction. II. Alterations of the metabolism and turnover of 131-I-low-density lipoproteins in hypothyroidism and thyrotoxicosis. , 1965, Clinical science.

[29]  R. Havel.  Approach to the patient with hyperlipidemia. , 1982, The Medical clinics of North America.

[30]  C. Packard,et al.  Apolipoprotein B metabolism in normal, type IV and type V hyperlipoproteinemic subjects. , 1980, Metabolism: clinical and experimental.

[31]  H. G. Morgan,et al.  Low density lipoprotein metabolism in a family of familial hypercholesterolemic patients. , 1976, Metabolism: clinical and experimental.

[32]  M. Kállai,et al.  The metabolic heterogeneity of human very low density lipoprotein triglyceride. , 1977, Metabolism: clinical and experimental.

[33]  P. Nestel,et al.  Sucrose-induced changes in VLDL- and LDL-B apoprotein removal rates. , 1979, Metabolism: clinical and experimental.

[34]  R. Havel,et al.  Secretion of lipoproteins from the liver of normal and Watanabe heritable hyperlipidemic rabbits. , 1983, Proceedings of the National Academy of Sciences of the United States of America.

[35]  G. Steiner,et al.  The independent synthesis of intermediate density lipoproteins in type III hyperlipoproteinemia. , 1982, Metabolism: clinical and experimental.

[36]  D. Steinberg,et al.  Dissociation of apoprotein B and triglyceride production in very-low-density lipoproteins. , 1980, The American journal of physiology.

[37]  R. Havel,et al.  Discoidal bilayer structure of nascent high density lipoproteins from perfused rat liver. , 1976, The Journal of clinical investigation.

[38]  D. Bilheimer,et al.  Delayed clearance of very low density and intermediate density lipoproteins with enhanced conversion to low density lipoprotein in WHHL rabbits. , 1982, Proceedings of the National Academy of Sciences of the United States of America.

[39]  D. Kipnis,et al.  Incorporation of SE75 Selenomethionine into a Protein Component of Plasma Very-Low-Density Lipoprotein in Man , 1972, Diabetes.

[40]  S. Grundy,et al.  Metabolic studies in familial hypercholesterolemia. Evidence for a gene-dosage effect in vivo. , 1979, The Journal of clinical investigation.

[41]  D. Steinberg,et al.  Effect of a high carbohydrate diet on apoprotein-B catabolism in man. , 1981, Metabolism: clinical and experimental.

[42]  J. Glomset,et al.  The metabolic role of lecithin: cholesterol acyltransferase: perspectives from pathology. , 1973, Advances in lipid research.

[43]  B. Lewis,et al.  Turnover of apolipoprotein-B in two subjects with familial hypobetalipoproteinemia. , 1977, Metabolism: clinical and experimental.

[44]  O. Faergeman,et al.  Characterization of remnants produced during the metabolism of triglyceride-rich lipoproteins of blood plasma and intestinal lymph in the rat. , 1975, The Journal of clinical investigation.

[45]  S. Eisenberg,et al.  Reversible modification of human plasma low density lipoproteins toward triglyceride-rich precursors. A mechanism for losing excess cholesterol esters. , 1982, The Journal of biological chemistry.

[46]  L. Rudel,et al.  Studies on the production of low density lipoproteins by perfused livers from nonhuman primates. Effect of dietary cholesterol. , 1983, The Journal of clinical investigation.

[47]  C. Matthews,et al.  The theory of tracer experiments with 131I-labelled plasma proteins. , 1957, Physics in medicine and biology.

[48]  R. Mahley,et al.  Receptor binding of cholesterol-induced high-density lipoproteins containing predominantly apoprotein E to cultured fibroblasts with mutations at the low-density lipoprotein receptor locus. , 1980, Biochemistry.

[49]  S. Eisenberg,et al.  Metabolsim of apoB and apoC lipoproteins in man: kinetic studies in normal and hyperlipoproteininemic subjects. , 1978, Journal of lipid research.

[50]  W. Fisher.  The characterization and occurrence of an Sf 20 serum lipoprotein. , 1970, The Journal of biological chemistry.

[51]  H. James,et al.  Low-density lipoprotein turnover studies in man. Evaluation of the integrated rate equations method, use of a whole-body radioactivity counter, and the problem of partial denaturation. , 1979, Clinical science.

[52]  M. Berman,et al.  The metabolism of apolipoprotein B in subjects with hypertriglyceridemia and polydisperse LDL. , 1980, Journal of lipid research.

[53]  T. Kita,et al.  Defective lipoprotein receptors and atherosclerosis. Lessons from an animal counterpart of familial hypercholesterolemia. , 1983, The New England journal of medicine.

[54]  B. Lewis,et al.  Intravenous fat tolerance. Correlation with very low density lipoprotein apoprotein B kinetics in man. , 1977, Atherosclerosis.

[55]  D. Bilheimer,et al.  The metabolism of very low density lipoprotein proteins. I. Preliminary in vitro and in vivo observations. , 1972, Biochimica et biophysica acta.