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. 1984 Dec;74(6):2164–2177. doi: 10.1172/JCI111643

Apolipoprotein A and B (Sf 100-400) metabolism during bezafibrate therapy in hypertriglyceridemic subjects.

J Shepherd, C J Packard, J M Stewart, R F Atmeh, R S Clark, D E Boag, K Carr, A R Lorimer, D Ballantyne, H G Morgan, et al.
PMCID: PMC425409  PMID: 6511921

Abstract

This study describes the effects of bezafibrate, an analogue of clofibrate, on the plasma lipid and lipoprotein profiles of 11 hypertriglyceridemic subjects and on their metabolism of apolipoproteins A-I, A-II, and B. The major action of the drug was to lower plasma triglyceride (by 58%; P less than 0.01). This was accompanied by a reduction in the level of very low density lipoprotein apoprotein B (Svedberg units of flotation [Sf] 60-400), whose mean residence time in the plasma fell threefold (from 3.4 to 1.0 h). Synthesis of the B protein in this fraction was not significantly altered, so the drug acts to accelerate the transit of very low density lipoprotein particles down the delipidation cascade. The metabolism of very low density lipoprotein remnant apoprotein B (Sf 12-100) changed little in response to treatment, although we detected a 30% increment (P less than 0.05) in the plasma concentration of this fraction. The mean residence time of these remnant particles in the plasma did not correlate with that of Sf 100-400 very low density lipoprotein apoprotein B, nor was this parameter altered by the drug. The most consistent and significant perturbation seen in the Sf 0-12 fraction (low density lipoprotein) was a reduction in the fractional catabolism of its apoprotein B moiety (26%; P less than 0.05). In those subjects who were grossly hypertriglyceridemic and who responded well to treatment, the level of this protein rose substantially owing to a combined increase in its synthesis and a reduction in its catabolism. In the group as a whole, high density lipoprotein cholesterol rose 13% (P less than 0.02), and detailed examination showed that this was associated with a small but significant increment in the plasma concentration of the high density lipoprotein subfraction 2. High density lipoprotein subfraction 3 also rose on the average, but this was not a consistent feature in all patients. The plasma concentrations and turnovers of the A proteins (A-I and A-II) were not significantly altered by bezafibrate therapy.

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Selected References

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

  1. BERMAN M. The formulation and testing of models. Ann N Y Acad Sci. 1963 May 10;108:182–194. doi: 10.1111/j.1749-6632.1963.tb13373.x. [DOI] [PubMed] [Google Scholar]
  2. Barter P. J., Nestel P. J., Carroll K. F. Precursors of plasma triglyceride fatty acid in humans. Effects of glucose consumption, clofibrate administration, and alcoholic fatty liver. Metabolism. 1972 Feb;21(2):117–124. doi: 10.1016/0026-0495(72)90063-7. [DOI] [PubMed] [Google Scholar]
  3. Behr S. R., Patsch J. R., Forte T., Bensadoun A. Plasma lipoprotein changes resulting from immunologically blocked lipolysis. J Lipid Res. 1981 Mar;22(3):443–451. [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. Berndt J., Gaumert R., Still J. Mode of action of the lipid-lowering agents, clofibrate and BM 15075, on cholesterol biosynthesis in rat liver. Atherosclerosis. 1978 Jun;30(2):147–152. doi: 10.1016/0021-9150(78)90057-6. [DOI] [PubMed] [Google Scholar]
  6. 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]
  7. 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]
  8. Fredrickson D. S., Levy R. I., Lees R. S. Fat transport in lipoproteins--an integrated approach to mechanisms and disorders. N Engl J Med. 1967 Feb 2;276(5):273–concl. doi: 10.1056/NEJM196702022760507. [DOI] [PubMed] [Google Scholar]
  9. 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]
  10. Grundy S. M., Mok H. Y. Colestipol, clofibrate, and phytosterols in combined therapy of hyperlipidemia. J Lab Clin Med. 1977 Feb;89(2):354–366. [PubMed] [Google Scholar]
  11. 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]
  12. Hunninghake D. B., Bell C., Olson L. Effect of colestipol and clofibrate, singly and in combination, on plasma lipid and lipoproteins in type IIb hyperlipoproteinemia. Metabolism. 1981 Jun;30(6):610–615. doi: 10.1016/0026-0495(81)90141-4. [DOI] [PubMed] [Google Scholar]
  13. Kane J. P. A rapid electrophoretic technique for identification of subunit species of apoproteins in serum lipoproteins. Anal Biochem. 1973 Jun;53(2):350–364. doi: 10.1016/0003-2697(73)90081-x. [DOI] [PubMed] [Google Scholar]
  14. Kane J. P., Sata T., Hamilton R. L., Havel R. J. Apoprotein composition of very low density lipoproteins of human serum. J Clin Invest. 1975 Dec;56(6):1622–1634. doi: 10.1172/JCI108245. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Kissebah A. H., Adams P. W., Harrigan P., Wynn V. The mechanism of action of clofibrate and tetranicotinoylfructose (Bradilan) on the kinetics of plasma free fatty acid and triglyceride transport in type IV and type V hypertriglyceridaemia. Eur J Clin Invest. 1974 Jun;4(3):163–174. doi: 10.1111/j.1365-2362.1974.tb00387.x. [DOI] [PubMed] [Google Scholar]
  16. 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]
  17. Lewis B., Chait A., Wootton I. D., Oakley C. M., Krikler D. M., Sigurdsson G., February A., Maurer B., Birkhead J. Frequency of risk factors for ischaemic heart-disease in a healthy British population. With particular reference to serum-lipoprotein levels. Lancet. 1974 Feb 2;1(7849):141–146. doi: 10.1016/s0140-6736(74)92438-6. [DOI] [PubMed] [Google Scholar]
  18. 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]
  19. Magill P., Rao S. N., Miller N. E., Nicoll A., Brunzell J., St Hilaire J., Lewis B. Relationships between the metabolism of high-density and very-low-density lipoproteins in man: studies of apolipoprotein kinetics and adipose tissue lipoprotein lipase activity. Eur J Clin Invest. 1982 Apr;12(2):113–120. doi: 10.1111/j.1365-2362.1982.tb00947.x. [DOI] [PubMed] [Google Scholar]
  20. Nerenberg S. T., Ganger C., DeMarco L. Rapid fluorescent "staining" of nondenatured protein bands in agar and polyacrylamide gels. Anal Biochem. 1971 Oct;43(2):564–574. doi: 10.1016/0003-2697(71)90288-0. [DOI] [PubMed] [Google Scholar]
  21. 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]
  22. OLIVER M. F. Reduction of serum-lipid and uric-acid levels by an orally active androsterone. Lancet. 1962 Jun 23;1(7243):1321–1323. doi: 10.1016/s0140-6736(62)92422-4. [DOI] [PubMed] [Google Scholar]
  23. Olsson A. G., Lang P. D. One-year study of the effect of bezafibrate on serum lipoprotein concentrations in hyperlipoproteinaemia. Atherosclerosis. 1978 Dec;31(4):429–433. doi: 10.1016/0021-9150(78)90138-7. [DOI] [PubMed] [Google Scholar]
  24. Olsson A. G., Rössner S., Walldius G., Carlson L. A., Lang P. D. Effect of BM 15.075 on lipoprotein concentrations in different types of hyperlipoproteinaemia. Atherosclerosis. 1977 Jul;27(3):279–287. doi: 10.1016/0021-9150(77)90037-5. [DOI] [PubMed] [Google Scholar]
  25. Packard C. J., Munro A., Lorimer A. R., Gotto A. M., Shepherd J. Metabolism of apolipoprotein B in large triglyceride-rich very low density lipoproteins of normal and hypertriglyceridemic subjects. J Clin Invest. 1984 Dec;74(6):2178–2192. doi: 10.1172/JCI111644. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. 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]
  27. Packard C. J., Stewart J. M., Third J. L., Morgan H. G., Lawrie T. D., Shepherd J. Effects of nicotinic acid therapy on high-density lipoprotein metabolism in type II and type IV hyperlipoproteinaemia. Biochim Biophys Acta. 1980 Apr 18;618(1):53–62. doi: 10.1016/0005-2760(80)90053-3. [DOI] [PubMed] [Google Scholar]
  28. 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]
  29. 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]
  30. Pertsemlidis D., Panveliwalla D., Ahrens E. H., Jr Effects of clofibrate and of an estrogen-progestin combination on fasting biliary lipids and cholic acid kinetics in man. Gastroenterology. 1974 Apr;66(4):565–573. [PubMed] [Google Scholar]
  31. 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]
  32. Shepherd J., Bicker S., Lorimer A. R., Packard C. J. Receptor-mediated low density lipoprotein catabolism in man. J Lipid Res. 1979 Nov;20(8):999–1006. [PubMed] [Google Scholar]
  33. Shepherd J., Packard C. J., Patsch J. R., Gotto A. M., Jr, Taunton O. D. Metabolism of apolipoproteins A-I and A-II and its influence on the high density lipoprotein subfraction distribution in males and females. Eur J Clin Invest. 1978 Jun;8(3):115–120. doi: 10.1111/j.1365-2362.1978.tb00823.x. [DOI] [PubMed] [Google Scholar]
  34. 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]
  35. Sodhi H. S., Kudchodkar B. J., Horlick L. Effect of chlorophenoxyisobutyrate on the metabolism of endogenous glycerides in man. Metabolism. 1971 Mar;20(3):309–318. doi: 10.1016/0026-0495(71)90115-6. [DOI] [PubMed] [Google Scholar]
  36. Soutar A. K., Myant N. B., Thompson G. R. The metabolism of very low density and intermediate density lipoproteins in patients with familial hypercholesterolaemia. Atherosclerosis. 1982 Jun;43(2-3):217–231. doi: 10.1016/0021-9150(82)90024-7. [DOI] [PubMed] [Google Scholar]
  37. Stephens R. E. High-resolution preparative SDS-polyacrylamide gel electrophoresis: fluorescent visualization and electrophoretic elution-concentration of protein bands. Anal Biochem. 1975 May 12;65(1-2):369–379. doi: 10.1016/0003-2697(75)90521-7. [DOI] [PubMed] [Google Scholar]
  38. 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]
  39. Taylor K. G., Holdsworth G., Galton D. J. Lipoprotein lipase and adipose tissue and plasma triglyceride clearance in patients with primary hypertriglyceridaemia. Eur J Clin Invest. 1980 Apr;10(2 Pt 1):133–138. doi: 10.1111/j.1365-2362.1980.tb02072.x. [DOI] [PubMed] [Google Scholar]
  40. Vessby B., Lithell H., Hellsing K., Ostlund-Lindqvist A. M., Gustafsson I. B., Boberg J., Ledermann H. Effects of bezafibrate on the serum lipoprotein lipid and apolipoprotein composition, lipoprotein triglyceride removal capacity and the fatty acid composition of the plasma lipid esters. Atherosclerosis. 1980 Oct;37(2):257–269. doi: 10.1016/0021-9150(80)90011-8. [DOI] [PubMed] [Google Scholar]
  41. 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]
  42. 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]
  43. Wolfe B. M., Kane J. P., Havel R. J., Brewster H. P. Mechanism of the hypolipemic effect of clofibrate in postabsorptive man. J Clin Invest. 1973 Sep;52(9):2146–2159. doi: 10.1172/JCI107399. [DOI] [PMC free article] [PubMed] [Google Scholar]

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