Abstract
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.
Full text
PDFSelected References
These references are in PubMed. This may not be the complete list of references from this article.
- Berman M., Hall M., 3rd, Levy R. I., Eisenberg S., Bilheimer D. W., Phair R. D., Goebel R. H. Metabolsim of apoB and apoC lipoproteins in man: kinetic studies in normal and hyperlipoproteininemic subjects. J Lipid Res. 1978 Jan;19(1):38–56. [PubMed] [Google Scholar]
- Bilheimer D. W., Eisenberg S., Levy R. I. The metabolism of very low density lipoprotein proteins. I. Preliminary in vitro and in vivo observations. Biochim Biophys Acta. 1972 Feb 21;260(2):212–221. doi: 10.1016/0005-2760(72)90034-3. [DOI] [PubMed] [Google Scholar]
- Bilheimer D. W., Stone N. J., Grundy S. M. Metabolic studies in familial hypercholesterolemia. Evidence for a gene-dosage effect in vivo. J Clin Invest. 1979 Aug;64(2):524–533. doi: 10.1172/JCI109490. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Bilheimer D. W., Watanabe Y., Kita T. Impaired receptor-mediated catabolism of low density lipoprotein in the WHHL rabbit, an animal model of familial hypercholesterolemia. Proc Natl Acad Sci U S A. 1982 May;79(10):3305–3309. doi: 10.1073/pnas.79.10.3305. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Brown M. S., Goldstein J. L. Lipoprotein receptors in the liver. Control signals for plasma cholesterol traffic. J Clin Invest. 1983 Sep;72(3):743–747. doi: 10.1172/JCI111044. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Calvert G. D., James H. M. 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. Clin Sci (Lond) 1979 Jan;56(1):71–76. doi: 10.1042/cs0560071. [DOI] [PubMed] [Google Scholar]
- Eaton R. P., Kipnis D. M. Incorporation of Se75 selenomethionine into a protein component of plasma very-low-density lipoprotein in man. Diabetes. 1972 Jun;21(6):744–753. doi: 10.2337/diab.21.6.744. [DOI] [PubMed] [Google Scholar]
- Egusa G., Beltz W. F., Grundy S. M., Howard B. V. Influence of obesity on the metabolism of apolipoprotein B in humans. J Clin Invest. 1985 Aug;76(2):596–603. doi: 10.1172/JCI112011. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Egusa G., Brady D. W., Grundy S. M., Howard B. V. 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. J Lipid Res. 1983 Sep;24(9):1261–1267. [PubMed] [Google Scholar]
- Eisenberg S., Bilheimer D. W., Levy R. I., Lindgren F. T. On the metabolic conversion of human plasma very low density lipoprotein to low density lipoprotein. Biochim Biophys Acta. 1973 Dec 20;326(3):361–377. doi: 10.1016/0005-2760(73)90138-0. [DOI] [PubMed] [Google Scholar]
- Fidge N. H., Poulis P. 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. J Lipid Res. 1978 Mar;19(3):342–349. [PubMed] [Google Scholar]
- Fisher W. R. The characterization and occurrence of an Sf 20 serum lipoprotein. J Biol Chem. 1970 Feb 25;245(4):877–884. [PubMed] [Google Scholar]
- Fisher W. R., Zech L. A., Bardalaye P., Warmke G., Berman M. The metabolism of apolipoprotein B in subjects with hypertriglyceridemia and polydisperse LDL. J Lipid Res. 1980 Aug;21(6):760–774. [PubMed] [Google Scholar]
- Ginsberg H. N., Le N. A., Melish J., Steinberg D., Brown W. V. Effect of a high carbohydrate diet on apoprotein-B catabolism in man. Metabolism. 1981 Apr;30(4):347–353. doi: 10.1016/0026-0495(81)90114-1. [DOI] [PubMed] [Google Scholar]
- Glomset J. A., Norum K. R. The metabolic role of lecithin: cholesterol acyltransferase: perspectives form pathology. Adv Lipid Res. 1973;11:1–65. [PubMed] [Google Scholar]
- Goldstein J. L., Kita T., Brown M. S. Defective lipoprotein receptors and atherosclerosis. Lessons from an animal counterpart of familial hypercholesterolemia. N Engl J Med. 1983 Aug 4;309(5):288–296. doi: 10.1056/NEJM198308043090507. [DOI] [PubMed] [Google Scholar]
- Grundy S. M., Mok H. Y. Chylomicron clearance in normal and hyperlipidemic man. Metabolism. 1976 Nov;25(11):1225–1239. doi: 10.1016/s0026-0495(76)80006-6. [DOI] [PubMed] [Google Scholar]
- Guo L. S., Hamilton R. L., Ostwald R., Havel R. J. Secretion of nascent lipoproteins and apolipoproteins by perfused livers of normal and cholesterol-fed guinea pigs. J Lipid Res. 1982 May;23(4):543–555. [PubMed] [Google Scholar]
- Hamilton R. L., Williams M. C., Fielding C. J., Havel R. J. Discoidal bilayer structure of nascent high density lipoproteins from perfused rat liver. J Clin Invest. 1976 Sep;58(3):667–680. doi: 10.1172/JCI108513. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Havel R. J. Approach to the patient with hyperlipidemia. Med Clin North Am. 1982 Mar;66(2):319–333. doi: 10.1016/s0025-7125(16)31423-7. [DOI] [PubMed] [Google Scholar]
- Hornick C. A., Kita T., Hamilton R. L., Kane J. P., Havel R. J. Secretion of lipoproteins from the liver of normal and Watanabe heritable hyperlipidemic rabbits. Proc Natl Acad Sci U S A. 1983 Oct;80(19):6096–6100. doi: 10.1073/pnas.80.19.6096. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Illingworth D. R. Metabolism of lipoproteins in nonhuman primates. Studies on the origin of low density lipoprotein apoprotein in the plasma of the squirrel monkey. Biochim Biophys Acta. 1975 Apr 18;388(1):38–51. doi: 10.1016/0005-2760(75)90060-0. [DOI] [PubMed] [Google Scholar]
- Innerarity T. L., Pitas R. E., Mahley R. W. Receptor binding of cholesterol-induced high-density lipoproteins containing predominantly apoprotein E to cultured fibroblasts with mutations at the low-density lipoprotein receptor locus. Biochemistry. 1980 Sep 2;19(18):4359–4365. doi: 10.1021/bi00559a032. [DOI] [PubMed] [Google Scholar]
- Janus E. D., Nicoll A. M., Turner P. R., Magill P., Lewis B. Kinetic bases of the primary hyperlipidaemias: studies of apolipoprotein B turnover in genetically defined subjects. Eur J Clin Invest. 1980 Apr;10(2 Pt 1):161–172. doi: 10.1111/j.1365-2362.1980.tb02076.x. [DOI] [PubMed] [Google Scholar]
- Janus E. D., Nicoll A., Wootton R., Turner P. R., Magill P. J., Lewis B. Quantitative studies of very low density lipoprotein: conversion to low density lipoprotein in normal controls and primary hyperlipidaemic states and the role of direct secretion of low density lipoprotein in heterozygous familial hypercholesterolaemia. Eur J Clin Invest. 1980 Apr;10(2 Pt 1):149–159. doi: 10.1111/j.1365-2362.1980.tb02075.x. [DOI] [PubMed] [Google Scholar]
- Kane J. P., Hardman D. A., Paulus H. E. Heterogeneity of apolipoprotein B: isolation of a new species from human chylomicrons. Proc Natl Acad Sci U S A. 1980 May;77(5):2465–2469. doi: 10.1073/pnas.77.5.2465. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Kesäniemi Y. A., Beltz W. F., Grundy S. M. Comparisons of metabolism of apolipoprotein B in normal subjects, obese patients, and patients with coronary heart disease. J Clin Invest. 1985 Aug;76(2):586–595. doi: 10.1172/JCI112010. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Kita T., Brown M. S., Bilheimer D. W., Goldstein J. L. Delayed clearance of very low density and intermediate density lipoproteins with enhanced conversion to low density lipoprotein in WHHL rabbits. Proc Natl Acad Sci U S A. 1982 Sep;79(18):5693–5697. doi: 10.1073/pnas.79.18.5693. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Langer T., Strober W., Levy R. I. The metabolism of low density lipoprotein in familial type II hyperlipoproteinemia. J Clin Invest. 1972 Jun;51(6):1528–1536. doi: 10.1172/JCI106949. [DOI] [PMC free article] [PubMed] [Google Scholar]
- MATTHEWS C. M. The theory of tracer experiments with 131I-labelled plasma proteins. Phys Med Biol. 1957 Jul;2(1):36–53. doi: 10.1088/0031-9155/2/1/305. [DOI] [PubMed] [Google Scholar]
- Marsh J. B. Apoproteins of the lipoproteins in a nonrecirculating perfusate of rat liver. J Lipid Res. 1976 Jan;17(1):85–89. [PubMed] [Google Scholar]
- Melish J., Le N. A., Ginsberg H., Steinberg D., Brown W. V. Dissociation of apoprotein B and triglyceride production in very-low-density lipoproteins. Am J Physiol. 1980 Nov;239(5):E354–E362. doi: 10.1152/ajpendo.1980.239.5.E354. [DOI] [PubMed] [Google Scholar]
- Mjos O. D., Faergeman O., Hamilton R. L., Havel R. J. Characterization of remnants produced during the metabolism of triglyceride-rich lipoproteins of blood plasma and intestinal lymph in the rat. J Clin Invest. 1975 Sep;56(3):603–615. doi: 10.1172/JCI108130. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Nakaya N., Chung B. H., Patsch J. R., Taunton O. D. Synthesis and release of low density lipoproteins by the isolated perfused pig liver. J Biol Chem. 1977 Nov 10;252(21):7530–7533. [PubMed] [Google Scholar]
- Nakaya N., Chung B. H., Taunton O. D. Synthesis of plasma lipoproteins by the isolated perfused liver from the fasted and fed pig. J Biol Chem. 1977 Aug 10;252(15):5258–5261. [PubMed] [Google Scholar]
- Nestel P. J., Reardon M., Fidge N. H. Sucrose-induced changes in VLDL- and LDL-B apoprotein removal rates. Metabolism. 1979 May;28(5):531–535. doi: 10.1016/0026-0495(79)90193-8. [DOI] [PubMed] [Google Scholar]
- Nicoll A., Sigurdsson G., Marsh A., Lewis B. Intravenous fat tolerance. Correlation with very low density lipoprotein apoprotein B kinetics in man. Atherosclerosis. 1977 Jan;26(1):17–22. doi: 10.1016/0021-9150(77)90135-6. [DOI] [PubMed] [Google Scholar]
- Noel S. P., Wong L., Dolphin P. J., Dory L., Rubenstein D. Secretion of cholesterol-rich lipoproteins by perfused livers of hypercholesterolemic rats. J Clin Invest. 1979 Aug;64(2):674–683. doi: 10.1172/JCI109508. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Packard C. J., Shepherd J., Joerns S., Gotto A. M., Taunton O. D. Apolipoprotein B metabolism in normal, type IV and type V hyperlipoproteinemic subjects. Metabolism. 1980 Mar;29(3):213–222. doi: 10.1016/0026-0495(80)90062-1. [DOI] [PubMed] [Google Scholar]
- Packard C. J., Third J. L., Shepherd J., Lorimer A. R., Morgan H. G., Lawrie T. D. Low density lipoprotein metabolism in a family of familial hypercholesterolemic patients. Metabolism. 1976 Sep;25(9):995–1006. doi: 10.1016/0026-0495(76)90129-3. [DOI] [PubMed] [Google Scholar]
- Pagnan A., Havel R. J., Kane J. P., Kotite L. Characterization of human very low density lipoproteins containing two electrophoretic populations: double pre-beta lipoproteinemia and primary dysbetalipoproteinemia. J Lipid Res. 1977 Sep;18(5):613–622. [PubMed] [Google Scholar]
- Phair R. D., Hammond M. G., Bowden J. A., Fried M., Fisher W. R., Berman M. Preliminary model for human lipoprotein metabolism in hyperlipoproteinemia. Fed Proc. 1975 Dec;34(13):2263–2270. [PubMed] [Google Scholar]
- Reardon M. F., Fidge N. H., Nestel P. J. Catabolism of very low density lipoprotein B apoprotein in man. J Clin Invest. 1978 Mar;61(3):850–860. doi: 10.1172/JCI108999. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Reardon M. F., Poapst M. E., Steiner G. The independent synthesis of intermediate density lipoproteins in type III hyperlipoproteinemia. Metabolism. 1982 May;31(5):421–427. doi: 10.1016/0026-0495(82)90228-1. [DOI] [PubMed] [Google Scholar]
- Shepherd J., Packard C. J., Grundy S. M., Yeshurun D., Gotto A. M., Jr, Taunton O. D. Effects of saturated and polyunsaturated fat diets on the chemical composition and metabolism of low density lipoproteins in man. J Lipid Res. 1980 Jan;21(1):91–99. [PubMed] [Google Scholar]
- Sigurdsson G., Nicoll A., Lewis B. Conversion of very low density lipoprotein to low density lipoprotein. A metabolic study of apolipoprotein B kinetics in human subjects. J Clin Invest. 1975 Dec;56(6):1481–1490. doi: 10.1172/JCI108229. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Sigurdsson G., Nicoll A., Lewis B. Metabolism of very low density lipoproteins in hyperlipidaemia: studies of apolipoprotein B kinetics in man. Eur J Clin Invest. 1976 Mar 31;6(2):167–177. doi: 10.1111/j.1365-2362.1976.tb00508.x. [DOI] [PubMed] [Google Scholar]
- Sigurdsson G., Nicoll A., Lewis B. Turnover of apolipoprotein-B in two subjects with familial hypobetalipoproteinemia. Metabolism. 1977 Jan;26(1):25–31. doi: 10.1016/0026-0495(77)90124-x. [DOI] [PubMed] [Google Scholar]
- Sniderman A., Thomas D., Marpole D., Teng B. Low density lipoprotein. A metabolic pathway for return of cholesterol to the splanchnic bed. J Clin Invest. 1978 Apr;61(4):867–873. doi: 10.1172/JCI109012. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Streja D., Kallai M. A., Steiner G. The metabolic heterogeneity of human very low density lipoprotein triglyceride. Metabolism. 1977 Dec;26(12):1333–1344. doi: 10.1016/0026-0495(77)90029-4. [DOI] [PubMed] [Google Scholar]
- Turner P. R., Miller N. E., Cortese C., Hazzard W., Coltart J., Lewis B. Splanchnic metabolism of plasma apolipoprotein B: studies of artery-hepatic vein differences of mass and radiolabel in fasted human subjects. J Clin Invest. 1981 Jun;67(6):1678–1686. doi: 10.1172/JCI110205. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Walton K. W., Scott P. J., Dykes P. W., Davies J. W. 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. Clin Sci. 1965 Oct;29(2):217–238. [PubMed] [Google Scholar]
- Zech L. A., Grundy S. M., Steinberg D., Berman M. Kinetic model for production and metabolism of very low density lipoprotein triglycerides. Evidence for a slow production pathway and results for normolipidemic subjects. J Clin Invest. 1979 Jun;63(6):1262–1273. doi: 10.1172/JCI109421. [DOI] [PMC free article] [PubMed] [Google Scholar]