Skip to main content
PMC home page
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1984 Aug;74(2):470–482. doi: 10.1172/JCI111444

Abnormalities in very low, low and high density lipoproteins in hypertriglyceridemia. Reversal toward normal with bezafibrate treatment.

S Eisenberg, D Gavish, Y Oschry, M Fainaru, R J Deckelbaum
PMCID: PMC370499  PMID: 6378975

Abstract

The effects of triglyceridemia on plasma lipoproteins were investigated in 16 hypertriglyceridemic (HTG) subjects (222-2,500 mg/dl) before and after the initiation of bezafibrate therapy. Bezafibrate caused a mean reduction of 56% in plasma triglyceride and increased the levels of lipoprotein and hepatic triglyceride lipases by 260 and 213%, respectively. The natures of very low density lipoprotein (VLDL), isolated at plasma density and of low and high density lipoprotein (LDL and HDL), separated by zonal ultracentrifugation, were determined. HTG-LDL appears as multiple fractions whereas HTG-HDL is seen predominantly as HDL3. HTG-VLDL is relatively poor in apoproteins and triglycerides but enriched in free and esterified cholesterol. HTG-LDL (main fraction) is depleted of free and esterified cholesterol but enriched in apoprotein and triglyceride. It is also denser and smaller than normal. HTG-HDL3 is denser than N-HDL3 and demonstrates compositional abnormalities similar to those of HTG-LDL. With the reduction of the VLDL mass, all abnormalities revert towards normal. This is accompanied by an increase in LDL-apoprotein B and cholesterol levels, which indicates an increased conversion of VLDL to LDL. Significant correlations between plasma triglyceride and the degree of all abnormalities are shown. The data obtained during treatment corroborate these relationships. The observations support the concept that most abnormalities reflect the degree of triglyceridemia. We suggest that plasma core-lipid transfer protein(s) is an effector of the abnormal cholesteryl ester distribution. Its prolonged action on increasingly large and slowly metabolized VLDL populations would entail a correspondingly excessive transfer of cholesteryl ester to VLDL and of triglyceride to LDL and HDL. It is calculated that, in moderate HTG, LDL and HDL contain only 50% of the normal cholesterol load. It is suggested that cholesteryl ester redistribution in HTG might be important in regulating metabolic events.

Full text

PDF
470

Images in this article

478Image
on p.478

Selected References

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

  1. BARTLETT G. R. Phosphorus assay in column chromatography. J Biol Chem. 1959 Mar;234(3):466–468. [PubMed] [Google Scholar]
  2. Barter P. J., Hopkins G. J. Relative rates of incorporation of esterified cholesterol into human very low density lipoproteins and low density lipoproteins. In vitro studies of two separate pathways. Biochim Biophys Acta. 1983 Mar 22;751(1):33–40. doi: 10.1016/0005-2760(83)90254-0. [DOI] [PubMed] [Google Scholar]
  3. Bengtsson G., Olivecrona T. Interaction of lipoprotein lipase with heparin-Sepharose. Evaluation of conditions for affinity binding. Biochem J. 1977 Oct 1;167(1):109–119. doi: 10.1042/bj1670109. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. 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]
  5. Boberg J., Boberg M., Gross R., Turner J. D., Augustin J., Brown W. V. Hepatic triglyceride and lipoprotein lipase activities of post-heparin plasma in normals and hypertriglyceridemics. Ups J Med Sci. 1979;84(3):215–227. doi: 10.3109/03009737909179158. [DOI] [PubMed] [Google Scholar]
  6. Breckenridge W. C., Little J. A., Steiner G., Chow A., Poapst M. Hypertriglyceridemia associated with deficiency of apolipoprotein C-II. N Engl J Med. 1978 Jun 8;298(23):1265–1273. doi: 10.1056/NEJM197806082982301. [DOI] [PubMed] [Google Scholar]
  7. Chajek T., Fielding C. J. Isolation and characterization of a human serum cholesteryl ester transfer protein. Proc Natl Acad Sci U S A. 1978 Jul;75(7):3445–3449. doi: 10.1073/pnas.75.7.3445. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Deckelbaum R. J., Eisenberg S., Oschry Y., Butbul E., Sharon I., Olivecrona T. Reversible modification of human plasma low density lipoproteins toward triglyceride-rich precursors. A mechanism for losing excess cholesterol esters. J Biol Chem. 1982 Jun 10;257(11):6509–6517. [PubMed] [Google Scholar]
  9. 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]
  10. Eisenberg S., Levy R. I. Lipoprotein metabolism. Adv Lipid Res. 1975;13:1–89. [PubMed] [Google Scholar]
  11. Fainaru M., Deckelbaum R., Golbus M. S. Apolipoproteins in human fetal blood and amniotic fluid in mid-trimester pregnancy. Prenat Diagn. 1981 Apr;1(2):125–129. doi: 10.1002/pd.1970010207. [DOI] [PubMed] [Google Scholar]
  12. Fainaru M., Glangeaud M. C., Eisenberg S. Radioimmunoassay of human high density lipoprotein apo-protein A-1. Biochim Biophys Acta. 1975 Apr 29;386(2):432–443. doi: 10.1016/0005-2795(75)90286-x. [DOI] [PubMed] [Google Scholar]
  13. Fredrickson D. S., Levy R. I., Lindgren F. T. A comparison of heritable abnormal lipoprotein patterns as defined by two different techniques. J Clin Invest. 1969 Nov;47(11):2446–2457. doi: 10.1172/JCI105927. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Gianturco S. H., Gotto A. M., Jr, Hwang S. L., Karlin J. B., Lin A. H., Prasad S. C., Bradley W. A. Apolipoprotein E mediates uptake of Sf 100-400 hypertriglyceridemic very low density lipoproteins by the low density lipoprotein receptor pathway in normal human fibroblasts. J Biol Chem. 1983 Apr 10;258(7):4526–4533. [PubMed] [Google Scholar]
  15. Glomset J. A. The plasma lecithins:cholesterol acyltransferase reaction. J Lipid Res. 1968 Mar;9(2):155–167. [PubMed] [Google Scholar]
  16. Grundy S. M., Mok H. Y., Zech L., Steinberg D., Berman M. Transport of very low density lipoprotein triglycerides in varying degrees of obesity and hypertriglyceridemia. J Clin Invest. 1979 Jun;63(6):1274–1283. doi: 10.1172/JCI109422. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. HAVEL R. J., EDER H. A., BRAGDON J. H. The distribution and chemical composition of ultracentrifugally separated lipoproteins in human serum. J Clin Invest. 1955 Sep;34(9):1345–1353. doi: 10.1172/JCI103182. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Hazzard W. R., Lindgren F. T., Bierman E. L. Very low density lipoprotein subfractions in a subject with broad-beta disease (Type 3 hyperlipoproteinemia) and a subject with endogenous lipemia (Type IV). Chemical composition and electrophoretic mobility. Biochim Biophys Acta. 1970 May 5;202(3):517–525. doi: 10.1016/0005-2760(70)90122-0. [DOI] [PubMed] [Google Scholar]
  19. Hopkins G. J., Barter P. J. Transfers of esterified cholesterol and triglyceride between high density and very low density lipoproteins: in vitro studies of rabbits and humans. Metabolism. 1980 Jun;29(6):546–550. doi: 10.1016/0026-0495(80)90080-3. [DOI] [PubMed] [Google Scholar]
  20. Huttunen J. K., Ehnholm C., Kekki M., Nikkilä E. A. Post-heparin plasma lipoprotein lipase and hepatic lipase in normal subjects and in patients with hypertriglyceridaemia: correlations to sex, age and various parameters of triglyceride metabolism. Clin Sci Mol Med. 1976 Apr;50(4):249–260. doi: 10.1042/cs0500249. [DOI] [PubMed] [Google Scholar]
  21. Huttunen J. K., Ehnholm C., Kinnunen P. K., Nikkilä E. A. An immunochemical method for the selective measurement of two triglyceride lipases in human postheparin plasma. Clin Chim Acta. 1975 Sep 16;63(3):335–347. doi: 10.1016/0009-8981(75)90055-8. [DOI] [PubMed] [Google Scholar]
  22. Ihm J., Ellsworth J. L., Chataing B., Harmony J. A. Plasma protein-facilitated coupled exchange of phosphatidylcholine and cholesteryl ester in the absence of cholesterol esterification. J Biol Chem. 1982 May 10;257(9):4818–4827. [PubMed] [Google Scholar]
  23. 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]
  24. Kaufmann N. A., Friedlander Y., Halfon S. T., Slater P. E., Dennis B. H., McClish D., Eisenberg S., Stein Y. Nutrient intake in Jerusalem--consumption in adults. Isr J Med Sci. 1982 Dec;18(12):1183–1197. [PubMed] [Google Scholar]
  25. Kekki M. Lipoprotein-lipase action determining plasma high density lipoprotein cholesterol level in adult normolipaemics. Atherosclerosis. 1980 Sep;37(1):143–150. doi: 10.1016/0021-9150(80)90102-1. [DOI] [PubMed] [Google Scholar]
  26. Kekki M. Plasma triglyceride turnover in 92 adult normolipaemic and 30 hypertriglyceridaemic subjects--the effect of age, synthesis rate and removal capacity on plasma triglyceride concentration. Ann Clin Res. 1980 Apr;12(2):64–76. [PubMed] [Google Scholar]
  27. Kissebah A. H., Alfarsi S., Adams P. W. Integrated regulation of very low density lipoprotein triglyceride and apolipoprotein-B kinetics in man: normolipemic subjects, familial hypertriglyceridemia and familial combined hyperlipidemia. Metabolism. 1981 Sep;30(9):856–868. doi: 10.1016/0026-0495(81)90064-0. [DOI] [PubMed] [Google Scholar]
  28. Kuchinskiene Z., Carlson L. A. Composition, concentration, and size of low density lipoproteins and of subfractions of very low density lipoproteins from serum of normal men and women. J Lipid Res. 1982 Jul;23(5):762–769. [PubMed] [Google Scholar]
  29. Kuusi T., Nikkilä E. A., Saarinen P., Varjo P., Laitinen L. A. Plasma high density lipoproteins HDL2, HDL3 and postheparin plasma lipases in relation to parameters of physical fitness. Atherosclerosis. 1982 Feb;41(2-3):209–219. doi: 10.1016/0021-9150(82)90186-1. [DOI] [PubMed] [Google Scholar]
  30. LOWRY O. H., ROSEBROUGH N. J., FARR A. L., RANDALL R. J. Protein measurement with the Folin phenol reagent. J Biol Chem. 1951 Nov;193(1):265–275. [PubMed] [Google Scholar]
  31. Lossow W. J., Lindgren F. T., Murchio J. C., Stevens G. R., Jensen L. C. Particle size and protein content of six fractions of the Sf 20 plasma lipoproteins isolated by density gradient centrifugation. J Lipid Res. 1969 Jan;10(1):68–76. [PubMed] [Google Scholar]
  32. Marcel Y. L., Vezina C., Milne R. W. Cholesteryl ester and apolipoprotein E transfer between human high density lipoproteins and chylomicrons. Biochim Biophys Acta. 1983 Feb 7;750(2):411–417. doi: 10.1016/0005-2760(83)90047-4. [DOI] [PubMed] [Google Scholar]
  33. Miller N. E., Rao S. N., Alaupovic P., Noble N., Slack J., Brunzell J. D., Lewis B. Familial apolipoprotein CII deficiency: plasma lipoproteins and apolipoproteins in heterozygous and homozygous subjects and the effects of plasma infusion. Eur J Clin Invest. 1981 Feb;11(1):69–76. doi: 10.1111/j.1365-2362.1981.tb01768.x. [DOI] [PubMed] [Google Scholar]
  34. Morton R. E., Zilversmit D. B. Purification and characterization of lipid transfer protein(s) from human lipoprotein-deficient plasma. J Lipid Res. 1982 Sep;23(7):1058–1067. [PubMed] [Google Scholar]
  35. 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]
  36. Myers L. H., Phillips N. R., Havel R. J. Mathematical evaluation of methods for estimation of the concentration of the major lipid components of human serum lipoproteins. J Lab Clin Med. 1976 Sep;88(3):491–505. [PubMed] [Google Scholar]
  37. Nichols A. V., Strisower E. H., Lindgren F. T., Adamson G. L., Coggiola E. L. Analysis of change in ultracentrifugal lipoprotein profiles following heparin and ethyl-p-chlorophenoxyisobutyrate administration. Clin Chim Acta. 1968 May;20(2):277–283. doi: 10.1016/0009-8981(68)90160-5. [DOI] [PubMed] [Google Scholar]
  38. Nikkilä E. A., Taskinen M. R., Kekki M. Relation of plasma high-density lipoprotein cholesterol to lipoprotein-lipase activity in adipose tissue and skeletal muscle of man. Atherosclerosis. 1978 Apr;29(4):497–501. doi: 10.1016/0021-9150(78)90178-8. [DOI] [PubMed] [Google Scholar]
  39. Oschry Y., Eisenberg S. Rat plasma lipoproteins: re-evaluation of a lipoprotein system in an animal devoid of cholesteryl ester transfer activity. J Lipid Res. 1982 Nov;23(8):1099–1106. [PubMed] [Google Scholar]
  40. 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]
  41. Patsch J. R., Sailer S., Kostner G., Sandhofer F., Holasek A., Braunsteiner H. Separation of the main lipoprotein density classes from human plasma by rate-zonal ultracentrifugation. J Lipid Res. 1974 Jul;15(4):356–366. [PubMed] [Google Scholar]
  42. Patsch W., Patsch J. R., Kostner G. M., Sailer S., Braunsteiner H. Isolation of subfractions of human very low density lipoproteins by zonal ultracentrifugation. J Biol Chem. 1978 Jul 25;253(14):4911–4915. [PubMed] [Google Scholar]
  43. Phillips N. R., Havel R. J., Kane J. P. Serum apolipoprotein A-I levels: relationship to lipoprotein lipid levels and selected demographic variables. Am J Epidemiol. 1982 Aug;116(2):302–313. doi: 10.1093/oxfordjournals.aje.a113414. [DOI] [PubMed] [Google Scholar]
  44. 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]
  45. Sata T., Havel R. J., Jones A. L. Characterization of subfractions of triglyceride-rich lipoproteins separated by gel chromatography from blood plasma of normolipemic and hyperlipemic humans. J Lipid Res. 1972 Nov;13(6):757–768. [PubMed] [Google Scholar]
  46. Schaefer E. J., Wetzel M. G., Bengtsson G., Scow R. O., Brewer H. B., Jr, Olivecrona T. Transfer of human lymph chylomicron constituents to other lipoprotein density fractions during in vitro lipolysis. J Lipid Res. 1982 Dec;23(9):1259–1273. [PubMed] [Google Scholar]
  47. 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]
  48. Sigurdsson G., Nicoll A., Lewis B. The metabolism of low density lipoprotein in endogenous hypertriglyceridaemia. Eur J Clin Invest. 1976 Mar 31;6(2):151–158. doi: 10.1111/j.1365-2362.1976.tb00506.x. [DOI] [PubMed] [Google Scholar]
  49. Stewart J. M., Packard C. J., Lorimer A. R., Boag D. E., Shepherd J. Effects of bezafibrate on receptor-mediated and receptor-independent low density lipoprotein catabolism in type II hyperlipoproteinaemic subjects. Atherosclerosis. 1982 Sep;44(3):355–365. doi: 10.1016/0021-9150(82)90010-7. [DOI] [PubMed] [Google Scholar]
  50. Tall A. R., Small D. M. Plasma high-density lipoproteins. N Engl J Med. 1978 Nov 30;299(22):1232–1236. doi: 10.1056/NEJM197811302992207. [DOI] [PubMed] [Google Scholar]
  51. Vakakis N., Redgrave T. G., Small D. M., Castelli W. P. Cholesterol content of red blood cells and low-density lipoproteins in hypertriglyceridemia. Biochim Biophys Acta. 1983 May 16;751(3):280–285. doi: 10.1016/0005-2760(83)90285-0. [DOI] [PubMed] [Google Scholar]
  52. Vessby B., Lithell H., Ledermann H. Elevated lipoprotein lipase activity in skeletal muscle tissue during treatment of hypertriglyceridaemic patients with bezafibrate. Atherosclerosis. 1982 Jul;44(1):113–118. doi: 10.1016/0021-9150(82)90057-0. [DOI] [PubMed] [Google Scholar]
  53. Wallinder L., Bengtsson G., Olivecrona T. Guinea pig very low density lipoproteins are a good substrate for lipoprotein lipase. Biochim Biophys Acta. 1979 Dec 18;575(3):458–462. doi: 10.1016/0005-2760(79)90115-2. [DOI] [PubMed] [Google Scholar]
  54. Weber K., Osborn M. The reliability of molecular weight determinations by dodecyl sulfate-polyacrylamide gel electrophoresis. J Biol Chem. 1969 Aug 25;244(16):4406–4412. [PubMed] [Google Scholar]
  55. Wilson D. E., Lees R. S. Metabolic relationships among the plasma lipoproteins. Reciprocal changes in the concentrations of very low and low density lipoproteins in man. J Clin Invest. 1972 May;51(5):1051–1057. doi: 10.1172/JCI106896. [DOI] [PMC free article] [PubMed] [Google Scholar]
  56. Zilversmit D. B., Hughes L. B., Balmer J. Stimulation of cholesterol ester exchange by lipoprotein-free rabbit plasma. Biochim Biophys Acta. 1975 Dec 17;409(3):393–398. doi: 10.1016/0005-2760(75)90036-3. [DOI] [PubMed] [Google Scholar]

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

RESOURCES