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. 1985 Jul;76(1):31–39. doi: 10.1172/JCI111962

Role of the kidneys in the metabolism of plasma mevalonate. Studies in humans and in rhesus monkeys.

D J McNamara, E H Ahrens Jr, T S Parker, K Morrissey
PMCID: PMC423696  PMID: 4019781

Abstract

Studies were carried out in humans and in rhesus monkeys to determine the role of the kidneys in the metabolism of circulating mevalonic acid (MVA). Following intravenous infusion of [14C]MVA and [3H]cholesterol, there was a rapid appearance of [14C]squalene in the kidneys that exhibited a significantly longer half-life than plasma or hepatic squalene. In man and in rhesus monkeys there was a rapid equilibration between newly synthesized cholesterol from MVA and exogenously administered cholesterol in all tissues except the kidneys, where the specific activity ratio of newly synthesized to exogenous cholesterol was significantly higher. Estimates of the quantitative metabolism of intravenously infused radiolabeled MVA in the monkey demonstrated that 23% was excreted in the urine, 67% metabolized to cholesterol (58% in nonrenal tissues and 9% in the kidneys), and 10% catabolized to CO2 and nonsteroid products. Measurements of MVA metabolism in anephric and uninephric patients demonstrate that, in the absence of renal uptake of MVA, exogenous and newly synthesized cholesterol achieve almost instantaneous equilibrium in the plasma; whereas in control subjects with normal renal function, this equilibration required at least 21 d for the two cholesterol decay curves to become parallel. These results suggest that the kidneys are solely responsible for the observed disequilibrium between newly synthesized and exogenous cholesterol; we suggest that this was due to the delayed release of newly synthesized cholesterol from the kidneys into the plasma compartment following intravenous infusion with radiolabeled MVA. The data document the importance of the kidneys in the metabolism of circulating MVA. However, calculation of the quantitative significance of this pathway in relation to whole body MVA metabolism indicates that renal metabolism of MVA accounts for approximately 0.1% of daily MVA turnover, and that alterations in this pathway due to any form of renal pathology would not result in significant changes in hepatic or whole body sterol synthesis rates. We urge caution in the use of radiolabeled MVA in long-term kinetic studies of sterol metabolism because our data show that the plasma compartment of MVA is not necessarily in isotopic equilibrium with tissue MVA.

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Selected References

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  1. Brady P. S., Scofield R. F., Mann S., Landau B. R. Effects of estrogen and testosterone on the metabolism of mevalonate by the shunt pathway. J Lipid Res. 1983 Sep;24(9):1168–1175. [PubMed] [Google Scholar]
  2. Brunengraber H., Weinstock S. B., Story D. L., Kopito R. R. Urinary clearance and metabolism of mevalonate by the isolataed perfused rat kidney. J Lipid Res. 1981 Aug;22(6):916–920. [PubMed] [Google Scholar]
  3. Cuzzopoli M., Hellström K., Svensson B. Effect of nephrectomy and cholesterol feeding on the metabolism of intravenously administered DL-mevalonate in the rat. Metabolism. 1972 Dec;21(12):1161–1170. doi: 10.1016/0026-0495(72)90111-4. [DOI] [PubMed] [Google Scholar]
  4. Edgren B., Hellström K. Lipid biosynthesis from DL (2- 14 C) mevalonic acid in intact mice and rabbits. Acta Physiol Scand. 1972 Oct;86(2):250–256. doi: 10.1111/j.1748-1716.1972.tb05330.x. [DOI] [PubMed] [Google Scholar]
  5. Edmond J., Popják G. Transfer of carbon atoms from mevalonate to n-fatty acids. J Biol Chem. 1974 Jan 10;249(1):66–71. [PubMed] [Google Scholar]
  6. Feingold K. R., Wiley M. H., MacRae G., Siperstein M. D. Influence of thyroid hormone status on mevalonate metabolism in rats. J Clin Invest. 1980 Oct;66(4):646–654. doi: 10.1172/JCI109900. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Feingold K. R., Wiley M. H., MacRae G., Siperstein M. D. The effect of decreased plasma cholesterol concentration on circulatinga mevalonate metabolism in rats. J Lipid Res. 1981 Aug;22(6):990–997. [PubMed] [Google Scholar]
  8. Feingold K. R., Wiley M. H., Searle G. L., Machida B. K., Siperstein M. D. Sex difference in human mevalonate metabolism. J Clin Invest. 1980 Aug;66(2):361–366. doi: 10.1172/JCI109864. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Fogelman A. M., Edmond J., Popjåk G. Metabolism of mevalonate in rats and man not leading to sterols. J Biol Chem. 1975 Mar 10;250(5):1771–1775. [PubMed] [Google Scholar]
  10. Fogelman A. M., Edmond J., Popjåk G. Metabolism of mevalonate in rats and man not leading to sterols. J Biol Chem. 1975 Mar 10;250(5):1771–1775. [PubMed] [Google Scholar]
  11. Golper T. A., Swartz S. H. Impaired renal mevalonate metabolism in nephrotic syndrome: a stimulus for increased hepatic cholesterogenesis independent of GFR and hypoalbuminemia. Metabolism. 1982 May;31(5):471–476. doi: 10.1016/0026-0495(82)90236-0. [DOI] [PubMed] [Google Scholar]
  12. Hellstrom K. H., Siperstein M. D., Bricker L. A., Luby L. J. Studies of the in vivo metabolism of mevalonic acid in the normal rat. J Clin Invest. 1973 Jun;52(6):1303–1313. doi: 10.1172/JCI107301. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Kekki M., Miettinen T. A., Wahlström B. Measurement of cholesterol synthesis in kinetically defined pools using fecal steroid analysis and double labeling technique in man. J Lipid Res. 1977 Jan;18(1):99–114. [PubMed] [Google Scholar]
  14. Kopito R. R., Brunengraber H. (R)-mevalonate excretion in human and rat urines. Proc Natl Acad Sci U S A. 1980 Oct;77(10):5738–5740. doi: 10.1073/pnas.77.10.5738. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Kopito R. R., Weinstock S. B., Freed L. E., Murray D. M., Brunengraber H. Metabolism of plasma mevalonate in rats and humans. J Lipid Res. 1982 May;23(4):577–583. [PubMed] [Google Scholar]
  16. Liu G. C., Ahrens E. H., Jr, Schreibman P. H., Crouse J. R. Measurement of squalene in human tissues and plasma: validation and application. J Lipid Res. 1976 Jan;17(1):38–45. [PubMed] [Google Scholar]
  17. Liu G. C., Ahrens E. H., Jr, Schreibman P. H., Samuel P., McNamara D. J., Crouse J. R. Measurement of cholesterol synthesis in man by isotope kinetics of squalene. Proc Natl Acad Sci U S A. 1975 Nov;72(11):4612–4616. doi: 10.1073/pnas.72.11.4612. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. McNamara D. J., Ahrens E. H., Jr, Samuel P., Crouse J. R. Measurement of daily cholesterol synthesis rates in man by assay of the fractional conversion of mevalonic acid to cholesterol. Proc Natl Acad Sci U S A. 1977 Jul;74(7):3043–3046. doi: 10.1073/pnas.74.7.3043. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Parker T. S., McNamara D. J., Brown C. D., Kolb R., Ahrens E. H., Jr, Alberts A. W., Tobert J., Chen J., De Schepper P. J. Plasma mevalonate as a measure of cholesterol synthesis in man. J Clin Invest. 1984 Sep;74(3):795–804. doi: 10.1172/JCI111495. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Parker T. S., McNamara D. J., Brown C., Garrigan O., Kolb R., Batwin H., Ahrens E. H., Jr Mevalonic acid in human plasma: relationship of concentration and circadian rhythm to cholesterol synthesis rates in man. Proc Natl Acad Sci U S A. 1982 May;79(9):3037–3041. doi: 10.1073/pnas.79.9.3037. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Popják G., Boehm G., Parker T. S., Edmond J., Edwards P. A., Fogelman A. M. Determination of mevalonate in blood plasma in man and rat. Mevalonate "tolerance" tests in man. J Lipid Res. 1979 Aug;20(6):716–728. [PubMed] [Google Scholar]
  22. Righetti M., Wiley M. H., Murrill P. A., Siperstein M. D. The in vitro metabolism of mevalonate by sterol and non-sterol pathways. J Biol Chem. 1976 May 10;251(9):2716–2721. [PubMed] [Google Scholar]
  23. Schwartz C. C., Berman M., Vlahcevic Z. R., Halloran L. G., Gregory D. H., Swell L. Multicompartmental analysis of cholesterol metabolism in man. Characterization of the hepatic bile acid and biliary cholesterol precursor sites. J Clin Invest. 1978 Feb;61(2):408–423. doi: 10.1172/JCI108952. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Weinstock S. B., Kopito R. R., Endemann G., Tomera J. F., Marinier E., Murray D. M., Brunengraber H. The shunt pathway of mevalonate metabolism in the isolated perfused rat liver. J Biol Chem. 1984 Jul 25;259(14):8939–8944. [PubMed] [Google Scholar]
  25. Wiley M. H., Feingold K. R., Howton M. M., Siperstein M. D. The effect of diabetes on mevalonate metabolism in the rat. Diabetologia. 1982 Feb;22(2):118–121. doi: 10.1007/BF00254840. [DOI] [PubMed] [Google Scholar]
  26. Wiley M. H., Howton M. M., Siperstein M. D. Sex differences in the sterol and nonsterol metabolism of mevalonate. J Biol Chem. 1979 Feb 10;254(3):837–842. [PubMed] [Google Scholar]
  27. Wiley M. H., Howton M. M., Siperstein M. D. The quantitative role of the kidneys in the in vivo metabolism of mevalonate. J Biol Chem. 1977 Jan 25;252(2):548–554. [PubMed] [Google Scholar]

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