Skip to main content
NCBI home page
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1985 Feb;75(2):710–721. doi: 10.1172/JCI111751

Effect of heparin-induced lipolysis on the distribution of apolipoprotein e among lipoprotein subclasses. Studies with patients deficient in hepatic triglyceride lipase and lipoprotein lipase.

A Rubinstein, J C Gibson, J R Paterniti Jr, G Kakis, A Little, H N Ginsberg, W V Brown
PMCID: PMC423564  PMID: 3973025

Abstract

In normal subjects, apolipoprotein E (apo E) is present on very low density lipoproteins (VLDL) (fraction I) and on particles of a size intermediate between VLDL and low density lipoproteins (LDL) (fraction II). The major portion of apo E is, however, on particles smaller than LDL but larger than the average high density lipoproteins (HDL) (fraction III). To investigate the possible role of the vascular lipases in determining this distribution of apo E among the plasma lipoproteins, we studied subjects with primary deficiency of either hepatic lipase or of lipoprotein lipase and compared them with normal subjects. Subjects with familial hepatic triglyceride lipase deficiency (n = 2) differ markedly from normal in that fraction II is the dominant apo E-containing group of lipoproteins. When lipolysis of VLDL was enhanced in these subjects upon release of lipoprotein lipase by intravenous heparin, a shift of the apo E from VLDL into fractions II and III was observed. In contrast, apolipoproteins CII and CIII (apo CII and CIII, respectively) did not accumulate in intermediate-sized particles but were shifted markedly from triglyceride rich lipoproteins to HDL after treatment with heparin. In subjects with primary lipoprotein lipase deficiency (n = 4), apo E was confined to fractions I and III. Release of hepatic triglyceride lipase by heparin injection in these subjects produced a shift of apo E from fraction I to III with no significant increase in fraction II. This movement of apo E from large VLDL and chylomicron-sized particles occurred with little hydrolysis of triglyceride and no significant shift of apo CII or CIII into HDL from triglyceride rich lipoproteins. When both lipoprotein lipase and hepatic triglyceride lipase were released by intravenous heparin injection into normal subjects (n = 3), fraction I declined and the apo E content of fraction III increased by an equivalent amount. Either moderate or no change was noted in the intermediate sized particles (fraction II). These data strongly support the hypothesis that fraction II is the product of the action of lipoprotein lipase upon triglyceride rich lipoproteins and is highly dependent on hepatic triglyceride lipase for its further catabolism. In addition, the hydrolysis by hepatic triglyceride lipase of triglyceride rich lipoproteins in general results in a preferential loss of apo E and its transfer to a specific group of large HDL.

Full text

PDF
710

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Abrams J. J., Grundy S. M., Ginsberg H. Metabolism of plasma triglycerides in hypothyroidism and hyperthyroidism in man. J Lipid Res. 1981 Feb;22(2):307–322. [PubMed] [Google Scholar]
  2. Allain C. C., Poon L. S., Chan C. S., Richmond W., Fu P. C. Enzymatic determination of total serum cholesterol. Clin Chem. 1974 Apr;20(4):470–475. [PubMed] [Google Scholar]
  3. Baginsky M. L., Brown W. V. A new method for the measurement of lipoprotein lipase in postheparin plasma using sodium dodecyl sulfate for the inactivation of hepatic triglyceride lipase. J Lipid Res. 1979 May;20(4):548–556. [PubMed] [Google Scholar]
  4. Berry E. M., Aldini R., Bar-On H., Eisenberg S. Role of the liver in the degradation of very low density lipoproteins: a study of lipolysis by heparin releasable liver lipase and uptake during isolated rat liver perfusion. Eur J Clin Invest. 1981 Jun;11(3):151–159. doi: 10.1111/j.1365-2362.1981.tb01834.x. [DOI] [PubMed] [Google Scholar]
  5. Blum C. B., Aron L., Sciacca R. Radioimmunoassay studies of human apolipoprotein E. J Clin Invest. 1980 Dec;66(6):1240–1250. doi: 10.1172/JCI109975. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Blum C. B. Dynamics of apolipoprotein E metabolism in humans. J Lipid Res. 1982 Dec;23(9):1308–1316. [PubMed] [Google Scholar]
  7. Breckenridge W. C., Little J. A., Alaupovic P., Wang C. S., Kuksis A., Kakis G., Lindgren F., Gardiner G. Lipoprotein abnormalities associated with a familial deficiency of hepatic lipase. Atherosclerosis. 1982 Nov;45(2):161–179. doi: 10.1016/0021-9150(82)90136-8. [DOI] [PubMed] [Google Scholar]
  8. Bucolo G., David H. Quantitative determination of serum triglycerides by the use of enzymes. Clin Chem. 1973 May;19(5):476–482. [PubMed] [Google Scholar]
  9. Bukberg P. R., Le N. A., Ginsberg H. N., Gibson J. C., Goldman L. C., Brown W. V. Direct measurement of apoprotein C-III specific activity in 125I-labeled very low density lipoproteins using immunoaffinity chromatography. J Lipid Res. 1983 Sep;24(9):1251–1260. [PubMed] [Google Scholar]
  10. Eisenberg S., Olivecrona T. Very low density lipoprotein. Fate of phospholipids, cholesterol, and apolipoprotein C during lipolysis in vitro. J Lipid Res. 1979 Jul;20(5):614–623. [PubMed] [Google Scholar]
  11. Finley P. R., Schifman R. B., Williams R. J., Lichti D. A. Cholesterol in high-density lipoprotein: use of Mg2+/dextran sulfate in its enzymic measurement. Clin Chem. 1978 Jun;24(6):931–933. [PubMed] [Google Scholar]
  12. Gibson J. C., Rubinstein A., Bukberg P. R., Brown W. V. Apolipoprotein E-enriched lipoprotein subclasses in normolipidemic subjects. J Lipid Res. 1983 Jul;24(7):886–898. [PubMed] [Google Scholar]
  13. Goldberg I. J., Le N. A., Paterniti J. R., Jr, Ginsberg H. N., Lindgren F. T., Brown W. V. Lipoprotein metabolism during acute inhibition of hepatic triglyceride lipase in the cynomolgus monkey. J Clin Invest. 1982 Dec;70(6):1184–1192. doi: 10.1172/JCI110717. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Gordon V., Innerarity T. L., Mahley R. W. Formation of cholesterol- and apoprotein E-enriched high density lipoproteins in vitro. J Biol Chem. 1983 May 25;258(10):6202–6212. [PubMed] [Google Scholar]
  15. Groot P. H., Scheek L. M., Jansen H. Liver lipase and high-density lipoprotein. Lipoprotein changes after incubation of human serum with rat liver lipase. Biochim Biophys Acta. 1983 May 16;751(3):393–400. doi: 10.1016/0005-2760(83)90298-9. [DOI] [PubMed] [Google Scholar]
  16. Grosser J., Schrecker O., Greten H. Function of hepatic triglyceride lipase in lipoprotein metabolism. J Lipid Res. 1981 Mar;22(3):437–442. [PubMed] [Google Scholar]
  17. Havel R. J., Kotite L., Vigne J. L., Kane J. P., Tun P., Phillips N., Chen G. C. Radioimmunoassay of human arginine-rich apolipoprotein, apoprotein E. Concentration in blood plasma and lipoproteins as affected by apoprotein E-3 deficiency. J Clin Invest. 1980 Dec;66(6):1351–1362. doi: 10.1172/JCI109988. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Heiss G., Tamir I., Davis C. E., Tyroler H. A., Rifkand B. M., Schonfeld G., Jacobs D., Frantz I. D., Jr Lipoprotein-cholesterol distributions in selected North American populations: the lipid research clinics program prevalence study. Circulation. 1980 Feb;61(2):302–315. doi: 10.1161/01.cir.61.2.302. [DOI] [PubMed] [Google Scholar]
  19. Jansen H., van Tol A., Hülsmann W. C. On the metabolic function of heparin-releasable liver lipase. Biochem Biophys Res Commun. 1980 Jan 15;92(1):53–59. doi: 10.1016/0006-291x(80)91518-1. [DOI] [PubMed] [Google Scholar]
  20. Kushwaha R. S., Hazzard W. R., Wahl P. W., Hoover J. J. Type III hyperlipoproteinemia: diagnosis in whole plasma by apolipoprotein-E immunoassay. Ann Intern Med. 1977 Nov;87(5):509–516. doi: 10.7326/0003-4819-87-5-509. [DOI] [PubMed] [Google Scholar]
  21. Kuusi T., Kinnunen P. K., Nikkilä E. A. Hepatic endothelial lipase antiserum influences rat plasma low and high density lipoproteins in vivo. FEBS Lett. 1979 Aug 15;104(2):384–388. doi: 10.1016/0014-5793(79)80858-3. [DOI] [PubMed] [Google Scholar]
  22. LaRosa J. C., Levy R. I., Brown W. V., Fredrickson D. S. Changes in high-density lipoprotein protein composition after heparin-induced lipolysis. Am J Physiol. 1971 Mar;220(3):785–791. doi: 10.1152/ajplegacy.1971.220.3.785. [DOI] [PubMed] [Google Scholar]
  23. Le N. A., Melish J. S., Roach B. C., Ginsberg H. N., Brown W. V. Direct measurement of apoprotein B specific activity in 125I-labeled lipoproteins. J Lipid Res. 1978 Jul;19(5):578–584. [PubMed] [Google Scholar]
  24. Mahley R. W. Atherogenic hyperlipoproteinemia. The cellular and molecular biology of plasma lipoproteins altered by dietary fat and cholesterol. Med Clin North Am. 1982 Mar;66(2):375–402. doi: 10.1016/s0025-7125(16)31426-2. [DOI] [PubMed] [Google Scholar]
  25. Mordasini R., Frey F., Flury W., Klose G., Greten H. Selective deficiency of hepatic triglyceride lipase in uremic patients. N Engl J Med. 1977 Dec 22;297(25):1362–1366. doi: 10.1056/NEJM197712222972502. [DOI] [PubMed] [Google Scholar]
  26. Murase T., Itakura H. Accumulation of intermediate density lipoprotein in plasma after intravenous administration of hepatic triglyceride lipase antibody in rats. Atherosclerosis. 1981 Jun;39(3):293–300. doi: 10.1016/0021-9150(81)90015-0. [DOI] [PubMed] [Google Scholar]
  27. Musliner T. A., Herbert P. N., Kingston M. J. Lipoprotein substrates of lipoprotein lipase and hepatic triacylglycerol lipase from human post-heparin plasma. Biochim Biophys Acta. 1979 Nov 21;575(2):277–288. doi: 10.1016/0005-2760(79)90029-8. [DOI] [PubMed] [Google Scholar]
  28. Müller P., Felin R., Lambrecht J., Agostini B., Wieland H., Rost W., Seidel D. Hypertriglyceridaemia secondary to liver disease. Eur J Clin Invest. 1974 Dec 5;4(6):419–428. doi: 10.1111/j.1365-2362.1974.tb00415.x. [DOI] [PubMed] [Google Scholar]
  29. Nestel P. J., Fidge N. H., Tan M. H. Increased lipoprotein-remnant formation in chronic renal failure. N Engl J Med. 1982 Aug 5;307(6):329–333. doi: 10.1056/NEJM198208053070601. [DOI] [PubMed] [Google Scholar]
  30. Nestel P. J., Huff M. W., Billington T., Fidge N. H. Changes in the plasma lipoprotein distribution of apolipoproteins C-II, C-III1, C-III2 and apolipoprotein B after heparin-induced lipolysis. Biochim Biophys Acta. 1982 Jul 20;712(1):94–102. doi: 10.1016/0005-2760(82)90089-3. [DOI] [PubMed] [Google Scholar]
  31. Nicoll A., Lewis B. Evaluation of the roles of lipoprotein lipase and hepatic lipase in lipoprotein metabolism: in vivo and in vitro studies in man. Eur J Clin Invest. 1980 Dec;10(6):487–495. doi: 10.1111/j.1365-2362.1980.tb02090.x. [DOI] [PubMed] [Google Scholar]
  32. Patsch J. R., Gotto A. M., Jr, Olivercrona T., Eisenberg S. Formation of high density lipoprotein2-like particles during lipolysis of very low density lipoproteins in vitro. Proc Natl Acad Sci U S A. 1978 Sep;75(9):4519–4523. doi: 10.1073/pnas.75.9.4519. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Quarfordt S. H., Frank A., Shames D. M., Berman M., Steinberg D. Very low density lipoprotein triglyceride transport in type IV hyperlipoproteinemia and the effects of carbohydrate-rich diets. J Clin Invest. 1970 Dec;49(12):2281–2297. doi: 10.1172/JCI106448. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Rao S. N., Cortese C., Miller N. E., Levy Y., Lewis B. Effects of heparin infusion on plasma lipoproteins in subjects with lipoprotein lipase deficiency. Evidence for a role of hepatic endothelial lipase in the metabolism of high-density lipoprotein subfractions in man. FEBS Lett. 1982 Dec 13;150(1):255–259. doi: 10.1016/0014-5793(82)81345-8. [DOI] [PubMed] [Google Scholar]
  35. Schneider W. J., Kovanen P. T., Brown M. S., Goldstein J. L., Utermann G., Weber W., Havel R. J., Kotite L., Kane J. P., Innerarity T. L. Familial dysbetalipoproteinemia. Abnormal binding of mutant apoprotein E to low density lipoprotein receptors of human fibroblasts and membranes from liver and adrenal of rats, rabbits, and cows. J Clin Invest. 1981 Oct;68(4):1075–1085. doi: 10.1172/JCI110330. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Tam S. P., Dory L., Rubinstein D. Fate of apolipoproteins C-1, C-iii, and E during lipolysis of human very low density lipoproteins in vitro. J Lipid Res. 1981 May;22(4):641–651. [PubMed] [Google Scholar]
  37. 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]
  38. Weidman S. W., Suarez B., Falko J. M., Witztum J. L., Kolar J., Raben M., Schonfeld G. Type III hyperlipoproteinemia: development of a VLDL ApoE gel isoelectric focusing technique and application in family studies. J Lab Clin Med. 1979 Apr;93(4):549–569. [PubMed] [Google Scholar]
  39. Weisgraber K. H., Mahley R. W., Assmann G. The rat arginine-rich apoprotein and its redistribution following injection of iodinated lipoproteins into normal and hypercholesterolemic rats. Atherosclerosis. 1977 Oct;28(2):121–140. doi: 10.1016/0021-9150(77)90150-2. [DOI] [PubMed] [Google Scholar]
  40. Weisgraber K. H., Rall S. C., Jr, Mahley R. W. Human E apoprotein heterogeneity. Cysteine-arginine interchanges in the amino acid sequence of the apo-E isoforms. J Biol Chem. 1981 Sep 10;256(17):9077–9083. [PubMed] [Google Scholar]

Articles from Journal of Clinical Investigation are provided here courtesy of American Society for Clinical Investigation

RESOURCES