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. 1992 Mar 15;282(Pt 3):753–757. doi: 10.1042/bj2820753

Mechanisms of fructose-induced hypertriglyceridaemia in the rat. Activation of hepatic pyruvate dehydrogenase through inhibition of pyruvate dehydrogenase kinase.

O J Park 1, D Cesar 1, D Faix 1, K Wu 1, C H Shackleton 1, M K Hellerstein 1
PMCID: PMC1130852  PMID: 1554357

Abstract

1. The effects of purified diets containing 70% glucose or 70% fructose on the activation state of hepatic pyruvate dehydrogenase (PDHa), activity of mitochondrial PDH kinase, plasma triacylglycerols (TG) and hepatic lipogenesis de novo in rats were measured. 2. Plasma TG were significantly increased in the fructose-fed compared with the glucose-fed group (125 +/- 45 mg/dl versus 57 +/- 19 mg/dl; P less than 0.002) after 3-5 weeks on the diet despite less daily food intake. 3. Hepatic PDHa in fructose-fed rats was 144% of the value in glucose-fed rats (15.4 +/- 1.2% versus 10.7 +/- 0.5%; P less than 0.002), whereas cardiac muscle PDHa was not different (45.5 +/- 6.6% versus 41.0 +/- 7.8%). 4. Intrinsic hepatic PDH kinase activity was decreased to 34% of glucose-fed values by fructose feeding (-k = 3.56 +/- 0.39 versus 10.41 +/- 1.85 min-1; P less than 0.005). 5. The fractional contribution to very-low-density-lipoprotein palmitate from hepatic lipogenesis de novo, measured by a stable-isotope mass-spectrometric method, was 10.49 +/- 2.42% (n = 8) in fructose-fed rats versus 5.55 +/- 1.38% (n = 9) in glucose-fed rats (P less than 0.05), and 2.66 +/- 2.39% (n = 3) in chow-fed rats (P less than 0.05 versus fructose-fed group). The absolute contribution to circulating TG from lipogenesis de novo was also significantly higher in the fructose-fed than in the glucose-fed group (14.9 +/- 5.1 mg/dl versus 2.9 +/- 0.6 mg/dl; P less than 0.05) 6. Portal insulin concentrations were significantly higher in the fructose-fed rats (206 +/- 49 mu-units/ml versus 81 +/- 15 mu-units/ml; P less than 0.05). 7. In conclusion, dietary fructose appears to have a specific activating effect on hepatic PDH, mediated at least in part by inhibition of PDH kinase. These results are consistent with increased flux through hepatic PDH and synthesis of new fat, not just increased re-esterification of non-esterified fatty acids.

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Selected References

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  1. Acheson K. J., Schutz Y., Bessard T., Anantharaman K., Flatt J. P., Jéquier E. Glycogen storage capacity and de novo lipogenesis during massive carbohydrate overfeeding in man. Am J Clin Nutr. 1988 Aug;48(2):240–247. doi: 10.1093/ajcn/48.2.240. [DOI] [PubMed] [Google Scholar]
  2. Anderson T. A. Recent trends in carbohydrate consumption. Annu Rev Nutr. 1982;2:113–132. doi: 10.1146/annurev.nu.02.070182.000553. [DOI] [PubMed] [Google Scholar]
  3. Bar-On H., Stein Y. Effect of glucose and fructose administration on lipid metabolism in the rat. J Nutr. 1968 Jan;94(1):95–105. doi: 10.1093/jn/94.1.95. [DOI] [PubMed] [Google Scholar]
  4. Boogaerts J. R., Malone-McNeal M., Archambault-Schexnayder J., Davis R. A. Dietary carbohydrate induces lipogenesis and very-low-density lipoprotein synthesis. Am J Physiol. 1984 Jan;246(1 Pt 1):E77–E83. doi: 10.1152/ajpendo.1984.246.1.E77. [DOI] [PubMed] [Google Scholar]
  5. Carmona A., Freedland R. A. Comparison among the lipogenic potential of various substrates in rat hepatocytes: the differential effects of fructose-containing diets on hepatic lipogenesis. J Nutr. 1989 Sep;119(9):1304–1310. doi: 10.1093/jn/119.9.1304. [DOI] [PubMed] [Google Scholar]
  6. Chevalier M. M., Wiley J. H., Leveille G. A. Effect of dietary fructose on fatty acid synthesis in adipose tissue and liver of the rat. J Nutr. 1972 Mar;102(3):337–342. doi: 10.1093/jn/102.3.337. [DOI] [PubMed] [Google Scholar]
  7. Davies D. R., Detheux M., Van Schaftingen E. Fructose 1-phosphate and the regulation of glucokinase activity in isolated hepatocytes. Eur J Biochem. 1990 Sep 11;192(2):283–289. doi: 10.1111/j.1432-1033.1990.tb19225.x. [DOI] [PubMed] [Google Scholar]
  8. Dietze G., Wicklmayr M., Mehnert H. Antiketogenic action of fructose in man. Diabetes. 1978 Jul;27(7):709–714. doi: 10.2337/diab.27.7.709. [DOI] [PubMed] [Google Scholar]
  9. FOSTER D. W., BLOOM B. The synthesis of fatty acids by rat liver slices in tritiated water. J Biol Chem. 1963 Mar;238:888–892. [PubMed] [Google Scholar]
  10. Hellerstein M. K., Christiansen M., Kaempfer S., Kletke C., Wu K., Reid J. S., Mulligan K., Hellerstein N. S., Shackleton C. H. Measurement of de novo hepatic lipogenesis in humans using stable isotopes. J Clin Invest. 1991 May;87(5):1841–1852. doi: 10.1172/JCI115206. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Hellerstein M. K. Relationship between precursor enrichment and ratio of excess M2/excess M1 isotopomer frequencies in a secreted polymer. J Biol Chem. 1991 Jun 15;266(17):10920–10924. [PubMed] [Google Scholar]
  12. Hellerstein M. K., Wu K., Kaempfer S., Kletke C., Shackleton C. H. Sampling the lipogenic hepatic acetyl-CoA pool in vivo in the rat. Comparison of xenobiotic probe to values predicted from isotopomeric distribution in circulating lipids and measurement of lipogenesis and acetyl-CoA dilution. J Biol Chem. 1991 Jun 15;266(17):10912–10919. [PubMed] [Google Scholar]
  13. Hill P. Effect of fructose on rat lipids. Lipids. 1970 Jul;5(7):621–627. doi: 10.1007/BF02531341. [DOI] [PubMed] [Google Scholar]
  14. Hirano T., Mamo J., Poapst M., Steiner G. Very-low-density lipoprotein triglyceride kinetics in acute and chronic carbohydrate-fed rats. Am J Physiol. 1988 Sep;255(3 Pt 1):E236–E240. doi: 10.1152/ajpendo.1988.255.3.E236. [DOI] [PubMed] [Google Scholar]
  15. Kaempfer S., Blackham M., Christiansen M., Wu K., Cesar D., Vary T., Hellerstein M. K. Fraction of hepatic cytosolic acetyl-CoA derived from glucose in vivo: relation to PDH phosphorylation state. Am J Physiol. 1991 Jun;260(6 Pt 1):E865–E875. doi: 10.1152/ajpendo.1991.260.6.E865. [DOI] [PubMed] [Google Scholar]
  16. Katz J., McGarry J. D. The glucose paradox. Is glucose a substrate for liver metabolism? J Clin Invest. 1984 Dec;74(6):1901–1909. doi: 10.1172/JCI111610. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Macdonald I. Influence of fructose and glucose on serum lipid levels in men and pre- and postmenopausal women. Am J Clin Nutr. 1966 May;18(5):369–372. doi: 10.1093/ajcn/18.5.369. [DOI] [PubMed] [Google Scholar]
  18. Marchington D. R., Kerbey A. L., Giardina M. G., Jones A. E., Randle P. J. Longer-term regulation of pyruvate dehydrogenase kinase in cultured rat hepatocytes. Biochem J. 1989 Jan 15;257(2):487–491. doi: 10.1042/bj2570487. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Mayes P. A., Laker M. E. Effects of acute and long-term fructose administration on liver lipid metabolism. Prog Biochem Pharmacol. 1986;21:33–58. [PubMed] [Google Scholar]
  20. McGarry J. D., Foster D. W. Regulation of hepatic fatty acid oxidation and ketone body production. Annu Rev Biochem. 1980;49:395–420. doi: 10.1146/annurev.bi.49.070180.002143. [DOI] [PubMed] [Google Scholar]
  21. McGarry J. D., Foster D. W. The regulation of ketogenesis from oleic acid and the influence of antiketogenic agents. J Biol Chem. 1971 Oct 25;246(20):6247–6253. [PubMed] [Google Scholar]
  22. Mistry S. C., Priestman D. A., Kerbey A. L., Randle P. J. Evidence that rat liver pyruvate dehydrogenase kinase activator protein is a pyruvate dehydrogenase kinase. Biochem J. 1991 May 1;275(Pt 3):775–779. doi: 10.1042/bj2750775. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Myles D. D., Strong P., Sugden M. C. Errors arising from the use of [1-14C]pyruvate to measure flux through the liver pyruvate dehydrogenase complex. Biochem J. 1984 Mar 15;218(3):997–998. doi: 10.1042/bj2180997. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Nestel P. J., Carroll K. F., Havenstein N. Plasma triglyceride response to carbohydrates, fats and caloric intake. Metabolism. 1970 Jan;19(1):1–18. doi: 10.1016/0026-0495(70)90112-5. [DOI] [PubMed] [Google Scholar]
  25. Nikkilä E. A., Ojala K. Induction of hyperglyceridemia by fructose in the rat. Life Sci. 1965 May;4(9):937–943. doi: 10.1016/0024-3205(65)90193-1. [DOI] [PubMed] [Google Scholar]
  26. Ontko J. A. Metabolism of free fatty acids in isolated liver cells. Factors affecting the partition between esterification and oxidation. J Biol Chem. 1972 Mar 25;247(6):1788–1800. [PubMed] [Google Scholar]
  27. PATKIN J. K., MASORO E. J. FATTY ACID SYNTHESIS IN NORMAL AND COLD-ACCLIMATED RATS. Can J Physiol Pharmacol. 1964 Jan;42:101–107. doi: 10.1139/y64-012. [DOI] [PubMed] [Google Scholar]
  28. Pettit F. H., Roche T. E., Reed L. J. Function of calcium ions in pyruvate dehydrogenase phosphatase activity. Biochem Biophys Res Commun. 1972 Oct 17;49(2):563–571. doi: 10.1016/0006-291x(72)90448-2. [DOI] [PubMed] [Google Scholar]
  29. Quastel J. H., Wheatley A. H. Oxidation of fatty acids in the liver. Biochem J. 1933;27(6):1752.1–171762. doi: 10.1042/bj0271752. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Radziuk J., McDonald T. J., Rubenstein D., Dupre J. Initial splanchnic extraction of ingested glucose in normal man. Metabolism. 1978 Jun;27(6):657–669. doi: 10.1016/0026-0495(78)90003-3. [DOI] [PubMed] [Google Scholar]
  31. Randle P. J. Fuel selection in animals. Biochem Soc Trans. 1986 Oct;14(5):799–806. doi: 10.1042/bst0140799. [DOI] [PubMed] [Google Scholar]
  32. Reaven G. M. Banting lecture 1988. Role of insulin resistance in human disease. Diabetes. 1988 Dec;37(12):1595–1607. doi: 10.2337/diab.37.12.1595. [DOI] [PubMed] [Google Scholar]
  33. Reid S., Shackleton C., Wu K., Kaempfer S., Hellerstein M. K. Liquid chromatography/mass spectrometry of plasma glucose and secreted glucuronate for metabolic studies in humans. Biomed Environ Mass Spectrom. 1990 Sep;19(9):535–540. doi: 10.1002/bms.1200190903. [DOI] [PubMed] [Google Scholar]
  34. Schwarz J. M., Schutz Y., Froidevaux F., Acheson K. J., Jeanprêtre N., Schneider H., Felber J. P., Jéquier E. Thermogenesis in men and women induced by fructose vs glucose added to a meal. Am J Clin Nutr. 1989 Apr;49(4):667–674. doi: 10.1093/ajcn/49.4.667. [DOI] [PubMed] [Google Scholar]
  35. Siess E. A., Wieland O. H. Phosphorylation state of cytosolic and mitochondrial adenine nucleotides and of pyruvate dehydrogenase in isolated rat liver cells. Biochem J. 1976 Apr 15;156(1):91–102. doi: 10.1042/bj1560091. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Simonson D. C., Tappy L., Jequier E., Felber J. P., DeFronzo R. A. Normalization of carbohydrate-induced thermogenesis by fructose in insulin-resistant states. Am J Physiol. 1988 Feb;254(2 Pt 1):E201–E207. doi: 10.1152/ajpendo.1988.254.2.E201. [DOI] [PubMed] [Google Scholar]
  37. Sleder J., Chen Y. D., Cully M. D., Reaven G. M. Hyperinsulinemia in fructose-induced hypertriglyceridemia in the rat. Metabolism. 1980 Apr;29(4):303–305. doi: 10.1016/0026-0495(80)90001-3. [DOI] [PubMed] [Google Scholar]
  38. Söling H. D., Bernhard G., Janson G. Interconversion of inactive to active pyruvate dehydrogenase in rat liver after fructose application in vivo. FEBS Lett. 1971 Mar 16;13(4):201–203. doi: 10.1016/0014-5793(71)80535-5. [DOI] [PubMed] [Google Scholar]
  39. Topping D. L., Mayes P. A. The immediate effects of insulin and fructose on the metabolism of the perfused liver. Changes in lipoprotein secretion, fatty acid oxidation and esterification, lipogenesis and carbohydrate metabolism. Biochem J. 1972 Jan;126(2):295–311. doi: 10.1042/bj1260295. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Van den Berghe G. Metabolic effects of fructose in the liver. Curr Top Cell Regul. 1978;13:97–135. doi: 10.1016/b978-0-12-152813-3.50008-2. [DOI] [PubMed] [Google Scholar]
  41. Waddell M., Fallon H. J. The effect of high-carbohydrate diets on liver triglyceride formation in the rat. J Clin Invest. 1973 Nov;52(11):2725–2731. doi: 10.1172/JCI107467. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Youn J. H., Kaslow H. R., Bergman R. N. Fructose effect to suppress hepatic glycogen degradation. J Biol Chem. 1987 Aug 25;262(24):11470–11477. [PubMed] [Google Scholar]
  43. Zakim D., Pardini R. S., Herman R. H., Sauberlich H. E. Mechanism for the differential effects of high carbohydrate diets on lipogenesis in rat liver. Biochim Biophys Acta. 1967 Oct 2;144(2):242–251. doi: 10.1016/0005-2760(67)90154-3. [DOI] [PubMed] [Google Scholar]
  44. Zavaroni I., Chen Y. D., Reaven G. M. Studies of the mechanism of fructose-induced hypertriglyceridemia in the rat. Metabolism. 1982 Nov;31(11):1077–1083. doi: 10.1016/0026-0495(82)90155-x. [DOI] [PubMed] [Google Scholar]

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