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. 1971 Nov;50(11):2339–2346. doi: 10.1172/JCI106732

Inhibition of hepatic triglyceride formation by clofibrate

Larry L Adams 1,2, William W Webb 1,2, Harold J Fallon 1,2
PMCID: PMC292176  PMID: 5096518

Abstract

The effect of clofibrate (CPIB) on hepatic glycerolipid formation has been studied in vivo and in vitro in the rat. Feeding 0.25% CPIB in laboratory chow significantly reduced serum triglyceride levels by 6 hr and concomitantly decreased the rate of glycerol-14C incorporation into hepatic and serum glycerides, in vivo. These changes persisted for at least 14 days. A similar decrease in serum triglyceride and glycerol incorporation into hepatic glycerides was observed in rats fed high glucose diets containing 0.25% CPIB. Serum glycerol was reduced by feeding CPIB for 14 days. The formation of diglyceride and triglyceride from 14C-sn-glycerol-3-P by rat liver homogenates was inhibited by addition of 1-40 mM CPIB to the reaction mixture. These results suggest that CPIB reduces hepatic glycerolipid synthesis, possibly by inhibition of one or more reactions in the esterification of sn-glycerol-3-P. This change may account for the early fall in serum triglyceride. At later time periods, serum glycerol levels fall and in some experiments, hepatic triglyceride content increases. Therefore, it is likely that additional metabolic alterations may contribute to the sustained hypotriglyceridemic effects of CPIB.

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Selected References

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

  1. AMENTA J. S. A RAPID CHEMICAL METHOD FOR QUANTIFICATION OF LIPIDS SEPARATED BY THIN-LAYER CHROMATOGRAPHY. J Lipid Res. 1964 Apr;5:270–272. [PubMed] [Google Scholar]
  2. AVOY D. R., SWYRYD E. A., GOULD R. G. EFFECTS OF ALPHA-P-CHLOROPHENOXYISOBUTYRYL ETHYL ESTER (CPIB) WITH AND WITHOUT ANDROSTERONE ON CHOLESTEROL BIOSYNTHESIS IN RAT LIVER. J Lipid Res. 1965 Jul;6:369–376. [PubMed] [Google Scholar]
  3. AZARNOFF D. L., TUCKER D. R., BARR G. A. STUDIES WITH ETHYL CHLOROPHENOXYISOBUTYRATE (CLOFIBRATE). Metabolism. 1965 Sep;14:959–965. doi: 10.1016/0026-0495(65)90111-3. [DOI] [PubMed] [Google Scholar]
  4. BAKER N., SCHOTZ M. C. USE OF MULTICOMPARTMENTAL MODELS TO MEASURE RATES OF TRIGLYCERIDE METABOLISM IN RATS. J Lipid Res. 1964 Apr;5:188–197. [PubMed] [Google Scholar]
  5. BEST M. M., DUNCAN C. H. HYPOLIPEMIA AND HEPATOMEGALY FROM ETHYL CHLOROPHENOXYISOBUTYRATE (CPIB) IN THE RAT. J Lab Clin Med. 1964 Oct;64:634–642. [PubMed] [Google Scholar]
  6. Baker N., Schotz M. C. Quantitative aspects of free fatty acid metabolism in the fasted rat. J Lipid Res. 1967 Nov;8(6):646–660. [PubMed] [Google Scholar]
  7. Barrett A. M. The effect of chlorophenoxyisobutyric acid on the release of free fatty acids from isolated adipose tissue in vitro. Br J Pharmacol Chemother. 1966 Feb;26(2):363–371. doi: 10.1111/j.1476-5381.1966.tb01916.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Bierman E. L., Brunzell J. D., Bagdade J. D., Lerner R. L., Hazzard W. R., Porte D., Jr On the mechanism of action of atromid-S on triglyceride transport in man. Trans Assoc Am Physicians. 1970;83:211–224. [PubMed] [Google Scholar]
  9. Cenedella R. J., Jarrell J. J., Saxe L. H. Effects of ethyl-p-chlorophenoxyisobutyrate, clofibrate, on the plasma and red blood cell free fatty acids of the rat. J Atheroscler Res. 1968 Nov-Dec;8(6):903–911. doi: 10.1016/s0368-1319(68)80004-3. [DOI] [PubMed] [Google Scholar]
  10. Duncan C. H., Best M. M. Influence of a terminal period of fasting on the serum and tissue lipid effects of ethyl chlorophenoxyisobutyrate (CPIB). Metabolism. 1968 Aug;17(8):681–689. doi: 10.1016/0026-0495(68)90052-8. [DOI] [PubMed] [Google Scholar]
  11. Fallon H. J., Gertman M., Kemp E. L. The effects of ethanol ingestion and choline deficiency on hepatic lecithin biosynthesis in the rat. Biochim Biophys Acta. 1969 Jul 29;187(1):94–104. doi: 10.1016/0005-2760(69)90136-2. [DOI] [PubMed] [Google Scholar]
  12. Fallon H. J., Kemp E. L. Effects of diet on hepatic triglyceride synthesis. J Clin Invest. 1968 Apr;47(4):712–719. doi: 10.1172/JCI105766. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Greene H. L., Herman R. H., Zakim D. The effect of clofibrate on rat tissue adenyl cyclase. Proc Soc Exp Biol Med. 1970 Sep;134(4):1035–1038. doi: 10.3181/00379727-134-34938. [DOI] [PubMed] [Google Scholar]
  14. Gross R. C., Eigenbrodt E. H., Farquhar J. W. Endogenous triglyceride turnover in liver and plasma of the dog. J Lipid Res. 1967 Mar;8(2):114–125. [PubMed] [Google Scholar]
  15. Hoak J. C., Connor W. E., Armstrong M. L., Warner E. D. Effect of clofibrate on serum and hepatic lipids in nephrotic rats. Lab Invest. 1968 Oct;19(4):370–375. [PubMed] [Google Scholar]
  16. Hunninghake D. B., Azarnoff D. L. Clofibrate effect on catecholamine-induced metabolic changes in humans. Metabolism. 1968 Jul;17(7):588–595. doi: 10.1016/0026-0495(68)90017-6. [DOI] [PubMed] [Google Scholar]
  17. Kokatnur M. G., Malcom G. T. Lipid lowering influence of ethyl p-chlorophenoxyisobutyrate in liver of rats fed high fat diets. Metabolism. 1970 Feb;19(2):120–128. [PubMed] [Google Scholar]
  18. 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]
  19. Lamb R. G., Fallon H. J. The formation of monoacylglycerophosphate from sn-glycerol 3-phosphate by a rat liver particulate preparation. J Biol Chem. 1970 Jun;245(12):3075–3083. [PubMed] [Google Scholar]
  20. Laurell S., Tibbling G. An enzymatic fluorometric micromethod for the determination of glycerol. Clin Chim Acta. 1966 Mar;13(3):317–322. doi: 10.1016/0009-8981(66)90210-5. [DOI] [PubMed] [Google Scholar]
  21. MARUO B., BENSON A. A. Cyclic glycerophosphate formation from the glycerolphosphatides. J Biol Chem. 1959 Feb;234(2):254–256. [PubMed] [Google Scholar]
  22. Maragoudakis M. E. Inhibition of hepatic acetyl coenzyme A carboxylase by hypolipidemic agents. J Biol Chem. 1969 Sep 25;244(18):5005–5013. [PubMed] [Google Scholar]
  23. Nestel P. J., Austin W. The effect of ethyl chlorophenoxyisobutyrate (CPIB) on the uptake of triglyceride fatty acids, activity of lipoprotein lipase and lipogenesis from glucose in fat tissue of rats. J Atheroscler Res. 1968 Sep-Oct;8(5):827–833. doi: 10.1016/s0368-1319(68)80045-6. [DOI] [PubMed] [Google Scholar]
  24. Newsholme E. A., Robinson J., Taylor K. A radiochemical enzymatic activity assay for glycerol kinase and hexokinase. Biochim Biophys Acta. 1967 Mar 15;132(2):338–346. doi: 10.1016/0005-2744(67)90153-2. [DOI] [PubMed] [Google Scholar]
  25. 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]
  26. Robinson J., Newsholme E. A. Some properties of hepatic glycerol kinase and their relation to the control of glycerol utilization. Biochem J. 1969 May;112(4):455–464. doi: 10.1042/bj1120455. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. THORP J. M., WARING W. S. Modification of metabolism and distribution of lipids by ethyl chlorophenoxyisobutyrate. Nature. 1962 Jun 9;194:948–949. doi: 10.1038/194948a0. [DOI] [PubMed] [Google Scholar]
  28. VAN HANDEL E., ZILVERSMIT D. B. Micromethod for the direct determination of serum triglycerides. J Lab Clin Med. 1957 Jul;50(1):152–157. [PubMed] [Google Scholar]
  29. Westerfeld W. W., Richert D. A., Ruegamer W. R. The role of the thyroid hormone in the effect of p-chlorophenoxyisobutyrate in rats. Biochem Pharmacol. 1968 Jun;17(6):1003–1016. doi: 10.1016/0006-2952(68)90359-6. [DOI] [PubMed] [Google Scholar]
  30. Wittels B., Bressler R. Lipid metabolism in the newborn heart. J Clin Invest. 1965 Oct;44(10):1639–1646. doi: 10.1172/JCI105270. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Young D. L., Lynen F. Enzymatic regulation of 3-sn-phosphatidylcholine and triacylglycerol synthesis in states of altered lipid metabolism. J Biol Chem. 1969 Jan 25;244(2):377–383. [PubMed] [Google Scholar]
  32. Zakim D., Herman R. H. The effect of clofibrate on the serum triglyceride concentration in normal males fed high-sucrose diets. J Atheroscler Res. 1969 Jul-Aug;10(1):91–95. doi: 10.1016/s0368-1319(69)80086-4. [DOI] [PubMed] [Google Scholar]

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