Skip to main content
PMC home page
British Journal of Pharmacology logoLink to British Journal of Pharmacology
. 1994 Jun;112(2):551–556. doi: 10.1111/j.1476-5381.1994.tb13109.x

Relationship between plasma lipids and palmitoyl-CoA hydrolase and synthetase activities with peroxisomal proliferation in rats treated with fibrates.

M Alegret 1, R Ferrando 1, M Vázquez 1, T Adzet 1, M Merlos 1, J C Laguna 1
PMCID: PMC1910384  PMID: 7915611

Abstract

1. The time-course of the effect of clofibrate (CFB), bezafibrate (BFB) and gemfibrozil (GFB) on lipid plasma levels and palmitoyl-CoA hydrolase and synthetase activities, as well as the correlations with the peroxisomal proliferation phenomenon have been studied in male Sprague-Dawley rats. 2. The administration of the three drugs caused a significant reduction in body weight gain, accompanied with a paradoxical increase in food intake in groups treated with BFB and GFB. 3. Drug treatment produced gross hepatomegaly and increase in peroxisomal beta-oxidation, and these parameters were strongly correlated. The order of potency was BFB > CFB > or = GFB. 4. Both plasma cholesterol (BFB approximately CFB > GFB) and triglyceride (BFB approximately GFB > CFB) levels were reduced in treated animals. There was an inverse correlation between these parameters and peroxisomal beta-oxidation, although the peroxisomal proliferation seemed to explain only a small part of the hypolipidemic effect observed. 5. Cytosolic and microsomal (but not mitochondrial) palmitoyl-CoA hydrolase activities were increased by the three drugs (BFB > CFB > GFB), probably by inducing the hydrolase I isoform, which is insensitive to inhibition by fibrates in vitro. The increased hydrolase activities were directly and strongly correlated with peroxisomal beta-oxidation. 6. Palmitoyl-CoA synthetase activity was also increased by the treatment with fibrates (BFB > CFB > GFB), probably as a consequence of the enhancement of hydrolase activities.(ABSTRACT TRUNCATED AT 250 WORDS)

Full text

PDF
551

Selected References

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

  1. Alegret M., Sánchez R., Adzet T., Merlos M., Laguna J. C. In vitro effect of clofibric acid derivatives on rat hepatic microsomal electron transport chains. Biochem Pharmacol. 1991 Oct 24;42(10):2057–2060. doi: 10.1016/0006-2952(91)90610-h. [DOI] [PubMed] [Google Scholar]
  2. Berge R. K., Aarsland A. Correlation between the cellular level of long-chain acyl-CoA, peroxisomal beta-oxidation, and palmitoyl-CoA hydrolase activity in rat liver. Are the two enzyme systems regulated by a substrate-induced mechanism? Biochim Biophys Acta. 1985 Nov 14;837(2):141–151. doi: 10.1016/0005-2760(85)90237-1. [DOI] [PubMed] [Google Scholar]
  3. Berge R. K., Bakke O. M. Changes in lipid metabolizing enzymes of hepatic subcellular fractions from rats treated with tiadenol and clofibrate. Biochem Pharmacol. 1981 Aug 15;30(16):2251–2256. doi: 10.1016/0006-2952(81)90095-2. [DOI] [PubMed] [Google Scholar]
  4. Berge R. K., Flatmark T., Osmundsen H. Enhancement of long-chain acyl-CoA hydrolase activity in peroxisomes and mitochondria of rat liver by peroxisomal proliferators. Eur J Biochem. 1984 Jun 15;141(3):637–644. doi: 10.1111/j.1432-1033.1984.tb08239.x. [DOI] [PubMed] [Google Scholar]
  5. Bodnar A. G., Rachubinski R. A. Characterization of the integral membrane polypeptides of rat liver peroxisomes isolated from untreated and clofibrate-treated rats. Biochem Cell Biol. 1991 Aug;69(8):499–508. doi: 10.1139/o91-074. [DOI] [PubMed] [Google Scholar]
  6. Bradford M. M. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem. 1976 May 7;72:248–254. doi: 10.1006/abio.1976.9999. [DOI] [PubMed] [Google Scholar]
  7. Bremer J., Osmundsen H., Christiansen R. Z., Borrebaek B. Clofibrate. Methods Enzymol. 1981;72:506–519. doi: 10.1016/s0076-6879(81)72040-8. [DOI] [PubMed] [Google Scholar]
  8. Cleary M. P. Effect of dehydroepiandrosterone treatment on liver metabolism in rats. Int J Biochem. 1990;22(3):205–210. doi: 10.1016/0020-711x(90)90331-v. [DOI] [PubMed] [Google Scholar]
  9. Desreumaux C., Dedonder E., Dewailly P., Sézille G., Fruchart J. C. Effects of unsaturated fatty acids in phospholipids on the in vitro activation of the lipoprotein lipase and the triglyceride lipase. Arzneimittelforschung. 1979;29(10):1581–1583. [PubMed] [Google Scholar]
  10. EARL D. C., KORNER A. THE ISOLATION AND PROPERTIES OF CARDIAC RIBOSOMES AND POLYSOMES. Biochem J. 1965 Mar;94:721–734. doi: 10.1042/bj0940721. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Esbenshade T. A., Kamanna V. S., Newman H. A., Tortorella V., Witiak D. T., Feller D. R. In vivo and in vitro peroxisome proliferation properties of selected clofibrate analogues in the rat. Structure-activity relationships. Biochem Pharmacol. 1990 Sep 15;40(6):1263–1274. doi: 10.1016/0006-2952(90)90392-x. [DOI] [PubMed] [Google Scholar]
  12. Frenkel R. A., Slaughter C. A., Orth K., Moomaw C. R., Hicks S. H., Snyder J. M., Bennett M., Prough R. A., Putnam R. S., Milewich L. Peroxisome proliferation and induction of peroxisomal enzymes in mouse and rat liver by dehydroepiandrosterone feeding. J Steroid Biochem. 1990 Feb;35(2):333–342. doi: 10.1016/0022-4731(90)90293-2. [DOI] [PubMed] [Google Scholar]
  13. Hawkins J. M., Jones W. E., Bonner F. W., Gibson G. G. The effect of peroxisome proliferators on microsomal, peroxisomal, and mitochondrial enzyme activities in the liver and kidney. Drug Metab Rev. 1987;18(4):441–515. doi: 10.3109/03602538708994130. [DOI] [PubMed] [Google Scholar]
  14. Katoh H., Kawashima Y., Watanuki H., Kozuka H., Isono H. Effects of clofibric acid and tiadenol on cytosolic long-chain acyl-CoA hydrolase and peroxisomal beta-oxidation in liver and extrahepatic tissues of rats. Biochim Biophys Acta. 1987 Jul 31;920(2):171–179. [PubMed] [Google Scholar]
  15. Kawashima Y., Katoh H., Kozuka H. Sex-related difference in the effect of clofibric acid on induction of two novel long-chain acyl-CoA hydrolases in rat liver. Biochim Biophys Acta. 1982 Jul 20;712(1):48–56. [PubMed] [Google Scholar]
  16. Kawashima Y., Katoh H., Nakajima S., Kozuka H. Induction of hepatic long-chain acyl-CoA hydrolase by clofibric acid administration. Biochim Biophys Acta. 1983 Jun 16;752(1):182–185. doi: 10.1016/0005-2760(83)90247-3. [DOI] [PubMed] [Google Scholar]
  17. Kłosiewicz-Latoszek L., Szostak W. B. Comparative studies on the influence of different fibrates on serum lipoproteins in endogenous hyperlipoproteinaemia. Eur J Clin Pharmacol. 1991;40(1):33–41. doi: 10.1007/BF00315136. [DOI] [PubMed] [Google Scholar]
  18. Lazarow P. B. Assay of peroxisomal beta-oxidation of fatty acids. Methods Enzymol. 1981;72:315–319. doi: 10.1016/s0076-6879(81)72021-4. [DOI] [PubMed] [Google Scholar]
  19. Lazarow P. B., Shio H., Leroy-Houyet M. A. Specificity in the action of hypolipidemic drugs: increase of peroxisomal beta-oxidation largely dissociated from hepatomegaly and peroxisome proliferation in the rat. J Lipid Res. 1982 Feb;23(2):317–326. [PubMed] [Google Scholar]
  20. McGuire E. J., Lucas J. A., Gray R. H., de la Iglesia F. A. Peroxisome induction potential and lipid-regulating activity in rats. Quantitative microscopy and chemical structure-activity relationships. Am J Pathol. 1991 Jul;139(1):217–229. [PMC free article] [PubMed] [Google Scholar]
  21. Nagi M. N., Laguna J. C., Cook L., Cinti D. L. Disruption of rat hepatic microsomal electron transport chains by the selenium-containing anti-inflammatory agent Ebselen. Arch Biochem Biophys. 1989 Feb 15;269(1):264–271. doi: 10.1016/0003-9861(89)90108-2. [DOI] [PubMed] [Google Scholar]
  22. Pill J., Völkl A., Hartig F., Fahimi H. D. Differences in the response of Sprague-Dawley and Lewis rats to bezafibrate: the hypolipidemic effect and the induction of peroxisomal enzymes. Arch Toxicol. 1992;66(5):327–333. doi: 10.1007/BF01973627. [DOI] [PubMed] [Google Scholar]
  23. Pourbaix S., Heller F., Harvengt C. Effect of fenofibrate and LF 2151 on hepatic peroxisomes in hamsters. Biochem Pharmacol. 1984 Nov 15;33(22):3661–3666. doi: 10.1016/0006-2952(84)90154-0. [DOI] [PubMed] [Google Scholar]
  24. Rao M. S., Musunuri S., Reddy J. K. Dehydroepiandrosterone-induced peroxisome proliferation in the rat liver. Pathobiology. 1992;60(2):82–86. doi: 10.1159/000163703. [DOI] [PubMed] [Google Scholar]
  25. Reddy J. K., Goel S. K., Nemali M. R., Carrino J. J., Laffler T. G., Reddy M. K., Sperbeck S. J., Osumi T., Hashimoto T., Lalwani N. D. Transcription regulation of peroxisomal fatty acyl-CoA oxidase and enoyl-CoA hydratase/3-hydroxyacyl-CoA dehydrogenase in rat liver by peroxisome proliferators. Proc Natl Acad Sci U S A. 1986 Mar;83(6):1747–1751. doi: 10.1073/pnas.83.6.1747. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Reddy J. K., Lalwai N. D. Carcinogenesis by hepatic peroxisome proliferators: evaluation of the risk of hypolipidemic drugs and industrial plasticizers to humans. Crit Rev Toxicol. 1983;12(1):1–58. doi: 10.3109/10408448309029317. [DOI] [PubMed] [Google Scholar]
  27. Sirtori C. R., Manzoni C., Lovati M. R. Mechanisms of lipid-lowering agents. Cardiology. 1991;78(3):226–235. doi: 10.1159/000174789. [DOI] [PubMed] [Google Scholar]
  28. Ståhlberg D., Angelin B., Einarsson K. Effects of treatment with clofibrate, bezafibrate, and ciprofibrate on the metabolism of cholesterol in rat liver microsomes. J Lipid Res. 1989 Jul;30(7):953–958. [PubMed] [Google Scholar]
  29. Sánchez R. M., Alegret M., Adzet T., Merlos M., Laguna J. C. Differential inhibition of long-chain acyl-CoA hydrolases by hypolipidemic drugs in vitro. Biochem Pharmacol. 1992 Feb 4;43(3):639–644. doi: 10.1016/0006-2952(92)90589-b. [DOI] [PubMed] [Google Scholar]
  30. Sánchez R. M., Viñals M., Alegret M., Vázquez M., Adzet T., Merlos M., Laguna J. C. Fibrates modify rat hepatic fatty acid chain elongation and desaturation in vitro. Biochem Pharmacol. 1993 Nov 17;46(10):1791–1796. doi: 10.1016/0006-2952(93)90584-j. [DOI] [PubMed] [Google Scholar]
  31. Sánchez R. M., Viñals M., Alegret M., Vázquez M., Adzet T., Merlos M., Laguna J. C. Inhibition of rat liver microsomal fatty acid chain elongation by gemfibrozil in vitro. FEBS Lett. 1992 Mar 23;300(1):89–92. doi: 10.1016/0014-5793(92)80170-l. [DOI] [PubMed] [Google Scholar]
  32. Sánchez R. M., Vázquez M., Alegret M., Viñals M., Adzet T., Merlos M., Laguna J. C. Cytosolic lipogenic enzymes: effect of fibric acid derivatives in vitro. Life Sci. 1993;52(2):213–222. doi: 10.1016/0024-3205(93)90142-p. [DOI] [PubMed] [Google Scholar]
  33. Vance J. E., Vance D. E. Lipoprotein assembly and secretion by hepatocytes. Annu Rev Nutr. 1990;10:337–356. doi: 10.1146/annurev.nu.10.070190.002005. [DOI] [PubMed] [Google Scholar]
  34. Vázquez M., Alegret M., Adzet T., Merlos M., Laguna J. C. Gemfibrozil modifies acyl composition of liver microsomal phospholipids from guinea-pigs without promoting peroxisomal proliferation. Biochem Pharmacol. 1993 Oct 19;46(8):1515–1518. doi: 10.1016/0006-2952(93)90121-c. [DOI] [PubMed] [Google Scholar]
  35. Yamada J., Sakuma M., Ikeda T., Fukuda K., Suga T. Characteristics of dehydroepiandrosterone as a peroxisome proliferator. Biochim Biophys Acta. 1991 Apr 17;1092(2):233–243. doi: 10.1016/0167-4889(91)90162-q. [DOI] [PubMed] [Google Scholar]

Articles from British Journal of Pharmacology are provided here courtesy of The British Pharmacological Society

RESOURCES