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. 1973 Sep;52(9):2146–2159. doi: 10.1172/JCI107399

Mechanism of the Hypolipemic Effect of Clofibrate in Postabsorptive Man

B M Wolfe 1,2, J P Kane 1,2, R J Havel 1,2, H P Brewster 1,2
PMCID: PMC333015  PMID: 4353773

Abstract

Splanchnic metabolism of triglycerides and other major substrates was studied in the postabsorptive state in normotriglyceridemic and hypertriglyceridemic human subjects who received ½ g of clofibrate four times daily for 3 wk. Transport in blood plasma of triglycerides produced in the splanchnic region was quantified by three methods: (a) measurement of the transsplanchnic gradient of 14C-labeled triglycerides during constant intravenous infusion of [1- 14C] palmitate (b) chemical measurement of the transplanchnic gradient in concentration of triglycerides of very low density lipoproteins; and (c) determination of clearance of 14C-labeled triglycerides in extrasplanchnic tissues. The first method measures only triglycerides derived from free fatty acids and the last two measure total splanchnic production. In hypertriglyceridemic subjects treated with clofibrate, average rates of total splanchnic production of triglycerides and production from free fatty acids were the same as those of comparable untreated subjects despite a consistent fall in plasma triglyceride levels. The hypotriglyceridemic effect of the drug was therefore accompanied by improved disposal of triglycerides in extrasplanchnic tissues. In treated normotriglyceridemic subjects, unlike their untreated counterparts, total splanchnic production was significantly higher than production from free fatty acids. Failure of clofibrate to reduce triglyceride levels in normotriglyceridemic subjects may have been related to increased total splanchnic production, coupled with improved extrasplanchnic disposal.

Systemic transport and net splanchnic uptake of free fatty acids were similar in treated and control subjects but the fraction of [1-14C]palmitate converted to acetoacetate in splanchnic tissues was significantly higher in treated subjects. Net splanchnic extraction of plasma amino acids that enter the glucogenic pathway via pyruvate was increased in treated subjects and their arterial concentrations were reduced.

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Selected References

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

  1. 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]
  2. Adams L. L., Webb W. W., Fallon H. J. Inhibition of hepatic triglyceride formation by clofibrate. J Clin Invest. 1971 Nov;50(11):2339–2346. doi: 10.1172/JCI106732. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Barrett A. M., Thorp J. M. Studies on the mode of action of clofibrate: effects on hormone-induced changes in plasma free fatty acids, cholesterol, phospholipids and total esterified fatty acids in rats and dogs. Br J Pharmacol Chemother. 1968 Feb;32(2):381–391. doi: 10.1111/j.1476-5381.1968.tb00980.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. 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]
  5. Basso L. V., Havel R. J. Hepatic metabolism of free fatty acids in normal and diabetic dogs. J Clin Invest. 1970 Mar;49(3):537–547. doi: 10.1172/JCI106264. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. 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]
  7. Block W. D., Markovs M. E., Steele B. F. Comparison between free amino acid levels in plasma deproteinated with picric acid and with sulfosalicylic acid. Proc Soc Exp Biol Med. 1966 Aug-Sep;122(4):1089–1091. doi: 10.3181/00379727-122-31333. [DOI] [PubMed] [Google Scholar]
  8. Boberg J., Carlson L. A., Freyschuss U. Determination of splanchnic secretion rate of plasma triglycerides and of total and splanchnic turnover of plasma free fatty acids in man. Eur J Clin Invest. 1972 Mar;2(3):123–132. doi: 10.1111/j.1365-2362.1972.tb00580.x. [DOI] [PubMed] [Google Scholar]
  9. Burch R. E., Curran G. L. Hepatic acetoacetyl-CoA deacylase activity in rats fed ethyl chlorophenoxyisobutyrate (CPIB). J Lipid Res. 1969 Nov;10(6):668–673. [PubMed] [Google Scholar]
  10. Cenedella R. J. Clofibrate and nafenopin (SU-13437): effects on plasma clearance and tissue distribution of chylomicron triglyceride in the dog. Lipids. 1972 Oct;7(10):644–652. doi: 10.1007/BF02533070. [DOI] [PubMed] [Google Scholar]
  11. 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]
  12. FARQUHAR J. W., GROSS R. C., WAGNER R. M., REAVEN G. M. VALIDATION OF AN INCOMPLETELY COUPLED TWO-COMPARTMENT NONRECYCLING CATENARY MODEL FOR TURNOVER OF LIVER AND PLASMA TRIGLYCERIDE IN MAN. J Lipid Res. 1965 Jan;6:119–134. [PubMed] [Google Scholar]
  13. Felig P., Wahren J. Amino acid metabolism in exercising man. J Clin Invest. 1971 Dec;50(12):2703–2714. doi: 10.1172/JCI106771. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Havel R. J. Caloric homeostasis and disorders of fuel transport. N Engl J Med. 1972 Dec 7;287(23):1186–1192. doi: 10.1056/NEJM197212072872307. [DOI] [PubMed] [Google Scholar]
  15. Havel R. J., Kane J. P., Balasse E. O., Segel N., Basso L. V. Splanchnic metabolism of free fatty acids and production of triglycerides of very low density lipoproteins in normotriglyceridemic and hypertriglyceridemic humans. J Clin Invest. 1970 Nov;49(11):2017–2035. doi: 10.1172/JCI106422. [DOI] [PMC free article] [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. Krebs H. A. The regulation of the release of ketone bodies by the liver. Adv Enzyme Regul. 1966;4:339–354. doi: 10.1016/0065-2571(66)90027-6. [DOI] [PubMed] [Google Scholar]
  18. Kurup C. K., Aithal H. N., Ramasarma T. Increase of hepatic mitochondria on administration of ethyl alpha-p-chlorophenoxyisobutyrate to the rat. Biochem J. 1970 Mar;116(5):773–779. doi: 10.1042/bj1160773. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Macmillan D. C., Oliver M. F., Simpson J. D., Tothill P. Effect of ethylchlorophenoxyisobutyrate on weight, plasma volume, total body-water, and free fatty acids. Lancet. 1965 Nov 6;2(7419):924–926. doi: 10.1016/s0140-6736(65)92902-8. [DOI] [PubMed] [Google Scholar]
  20. McGarry J. D., Foster D. W. Ketogenesis and cholesterol synthesis in normal and neoplastic tissues of the rat. J Biol Chem. 1969 Aug 10;244(15):4251–4256. [PubMed] [Google Scholar]
  21. Noble R. P. Electrophoretic separation of plasma lipoproteins in agarose gel. J Lipid Res. 1968 Nov;9(6):693–700. [PubMed] [Google Scholar]
  22. Persson B., Schröder G., Hood B. Lipoprotein lipase activity in human adipose tissue: assay methods. Relations to the serum triglyceride level in a normolipidemic population. The effect of ethyl chlorophenoxy isobutyrate. Atherosclerosis. 1972 Jul-Aug;16(1):37–49. doi: 10.1016/0021-9150(72)90006-8. [DOI] [PubMed] [Google Scholar]
  23. Platt D. S., Cockrill B. L. Changes in the liver concentrations of the nicotinamide adenine dinucleotide coenzymes and in the activities of oxidoreductase enzymes following treatment of the rat with ethyl chlorophenoxyisobutyrate (Atromid-S). Biochem Pharmacol. 1966 Jul;15(7):927–935. doi: 10.1016/0006-2952(66)90169-9. [DOI] [PubMed] [Google Scholar]
  24. Quarfordt S., Levy R. I., Fredrickson D. S. On thelipoprotein abnormality in type 3 hyperlipoproteinemia. J Clin Invest. 1971 Apr;50(4):754–761. doi: 10.1172/JCI106546. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Rifkind B. M. Effect of CPIB ester on plasma free fatty acid levels in man. Metabolism. 1966 Aug;15(8):673–675. doi: 10.1016/s0026-0495(66)80001-x. [DOI] [PubMed] [Google Scholar]
  26. Ryan W. G., Schwartz T. B. Dynamics of plasma triglyceride turnover in man. Metabolism. 1965 Dec;14(12):1243–1254. doi: 10.1016/s0026-0495(65)80004-x. [DOI] [PubMed] [Google Scholar]
  27. SKEGGS L. T., Jr An automatic method for colorimetric analysis. Am J Clin Pathol. 1957 Sep;28(3):311–322. doi: 10.1093/ajcp/28.3_ts.311. [DOI] [PubMed] [Google Scholar]
  28. Segal P., Roheim P. S., Eder H. A. Effect of clofibrate on lipoprotein metabolism in hyperlipidemic rats. J Clin Invest. 1972 Jul;51(7):1632–1638. doi: 10.1172/JCI106964. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. 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]
  30. Solberg H. E., Aas M., Daae L. N. The activity of the different carnitine acyltransferases in the liver of clofibrate-fed rats. Biochim Biophys Acta. 1972 Nov 30;280(3):434–439. doi: 10.1016/0005-2760(72)90249-4. [DOI] [PubMed] [Google Scholar]
  31. THORP J. M. AN EXPERIMENTAL APPROACH TO THE PROBLEM OF DISORDERED LIPID METABOLISM. J Atheroscler Res. 1963 Sep-Dec;3:351–360. doi: 10.1016/s0368-1319(63)80017-4. [DOI] [PubMed] [Google Scholar]
  32. Tolman E. L., Tepperman H. M., Tepperman J. Effect of ethyl p-chlorophenoxyisobutyrate on rat adipose lipoprotein lipase activity. Am J Physiol. 1970 May;218(5):1313–1318. doi: 10.1152/ajplegacy.1970.218.5.1313. [DOI] [PubMed] [Google Scholar]
  33. WALSER M., BODENLOS L. J. Urea metabolism in man. J Clin Invest. 1959 Sep;38:1617–1626. doi: 10.1172/JCI103940. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Wahren J., Felig P., Cerasi E., Luft R. Splanchnic and peripheral glucose and amino acid metabolism in diabetes mellitus. J Clin Invest. 1972 Jul;51(7):1870–1878. doi: 10.1172/JCI106989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. 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]
  36. White L. W. Regulation of hepatic cholesterol biosynthesis by clofibrate administration. J Pharmacol Exp Ther. 1971 Aug;178(2):361–370. [PubMed] [Google Scholar]
  37. 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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