Skip to main content
NCBI home page
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1984 Sep;74(3):795–804. doi: 10.1172/JCI111495

Plasma mevalonate as a measure of cholesterol synthesis in man.

T S Parker, D J McNamara, C D Brown, R Kolb, E H Ahrens Jr, A W Alberts, J Tobert, J Chen, P J De Schepper
PMCID: PMC425233  PMID: 6565710

Abstract

Measurement of mevalonic acid (MVA) concentrations in plasma or 24-h urine samples is shown to be useful in studies of the regulation of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase and cholesterol synthesis. Plasma MVA concentrations, measured either at 7-9 a.m. after an overnight fast, or throughout the 24-h cycle, were compared with cholesterol synthesis rates that were measured by the sterol balance method: plasma MVA concentrations were directly related to the rate of whole body cholesterol synthesis (r = 0.972; p less than 0.001; n = 18) over a tenfold range of cholesterol synthesis rates. Moreover, hourly examination of MVA concentrations throughout the day demonstrated that interventions such as fasting or cholesterol feeding cause suppression of the postmidnight diurnal rise in plasma MVA concentrations, with little change in the base-line of the rhythm. Thus, the daily rise and fall of plasma MVA appears to reflect changes in tissues and organs, such as the liver and intestine, that are known to be most sensitive to regulation by fasting or by dietary cholesterol. The hypothesis that short-term regulation of HMG-CoA reductase in tissues is quickly reflected by corresponding variations in plasma MVA was tested by using a specific inhibitor of HMG-CoA reductase, mevinolin, to block MVA synthesis. Mevinolin caused a dose-dependent lowering of plasma MVA after a single dose; and in patients who received the drug twice a day for 4 wk, it decreased 24-h urinary MVA output. Significant lowering of plasma cholesterol was achieved through administration of mevinolin at doses that only moderately limit MVA production.

Full text

PDF
795

Selected References

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

  1. AHRENS E. H., Jr, DOLE V. P., BLANKENHORN D. H. The use of orally-fed liquid formulas in metabolic studies. Am J Clin Nutr. 1954 Sep-Oct;2(5):336–342. doi: 10.1093/ajcn/2.5.336. [DOI] [PubMed] [Google Scholar]
  2. Alberts A. W., Chen J., Kuron G., Hunt V., Huff J., Hoffman C., Rothrock J., Lopez M., Joshua H., Harris E. Mevinolin: a highly potent competitive inhibitor of hydroxymethylglutaryl-coenzyme A reductase and a cholesterol-lowering agent. Proc Natl Acad Sci U S A. 1980 Jul;77(7):3957–3961. doi: 10.1073/pnas.77.7.3957. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Bensch W. R., Ingebritsen T. S., Diller E. R. Lack of correlation between the rate of cholesterol biosynthesis and the activity of 3-hydroxy-3-methylgutaryl coenzyme A reductase in rats and in fibroblasts treated with ML-236B. Biochem Biophys Res Commun. 1978 May 15;82(1):247–254. doi: 10.1016/0006-291x(78)90602-2. [DOI] [PubMed] [Google Scholar]
  4. Brown M. S., Goldstein J. L. Multivalent feedback regulation of HMG CoA reductase, a control mechanism coordinating isoprenoid synthesis and cell growth. J Lipid Res. 1980 Jul;21(5):505–517. [PubMed] [Google Scholar]
  5. 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]
  6. Davignon J., Simmonds W. J., Ahrens E. H. Usefulness of chromic oxide as an internal standard for balance studies in formula-fed patients and for assessment of colonic function. J Clin Invest. 1968 Jan;47(1):127–138. doi: 10.1172/JCI105703. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Dietschy J. M., Wilson J. D. Regulation of cholesterol metabolism. I. N Engl J Med. 1970 May 14;282(20):1128–1138. doi: 10.1056/NEJM197005142822005. [DOI] [PubMed] [Google Scholar]
  8. Edwards P. A., Edmond J., Fogelman A. M., Popjak G. Preferential uptake and utilization of mevalonolactone over mevalonate for sterol biosynthesis in isolated rat hepatocytes. Biochim Biophys Acta. 1977 Sep 28;488(3):493–501. doi: 10.1016/0005-2760(77)90207-7. [DOI] [PubMed] [Google Scholar]
  9. Edwards P. A., Muroya H., Gould R. G. In vivo demonstration of the circadian thythm of cholesterol biosynthesis in the liver and intestine of the rat. J Lipid Res. 1972 May;13(3):396–401. [PubMed] [Google Scholar]
  10. Endo A., Tsujita Y., Kuroda M., Tanzawa K. Effects of ML-236B on cholesterol metabolism in mice and rats: lack of hypocholesterolemic activity in normal animals. Biochim Biophys Acta. 1979 Nov 21;575(2):266–276. [PubMed] [Google Scholar]
  11. Fears R., Richards D. H., Ferres H. The effect of compactin, a potent inhibitor of 3-hydroxy-3-methylglutaryl coenzyme-A reductase activity, on cholesterogenesis and serum cholesterol levels in rats and chicks. Atherosclerosis. 1980 Apr;35(4):439–449. doi: 10.1016/0021-9150(80)90185-9. [DOI] [PubMed] [Google Scholar]
  12. Feingold K. R., Wiley M. H., MacRae G., Lear S., Moser A. H., Zsigmond G., Siperstein M. D. De novo sterologenesis in the intact rat. Metabolism. 1983 Jan;32(1):75–81. doi: 10.1016/0026-0495(83)90160-9. [DOI] [PubMed] [Google Scholar]
  13. GRUNDY S. M., AHRENS E. H., Jr, MIETTINEN T. A. QUANTITATIVE ISOLATION AND GAS--LIQUID CHROMATOGRAPHIC ANALYSIS OF TOTAL FECAL BILE ACIDS. J Lipid Res. 1965 Jul;6:397–410. [PubMed] [Google Scholar]
  14. Grundy S. M., Ahrens E. H., Jr, Davignon J. The interaction of cholesterol absorption and cholesterol synthesis in man. J Lipid Res. 1969 May;10(3):304–315. [PubMed] [Google Scholar]
  15. Grundy S. M., Ahrens E. H., Jr, Salen G. Dietary beta-sitosterol as an internal standard to correct for cholesterol losses in sterol balance studies. J Lipid Res. 1968 May;9(3):374–387. [PubMed] [Google Scholar]
  16. Grundy S. M., Ahrens E. H., Jr, Salen G. Interruption of the enterohepatic circulation of bile acids in man: comparative effects of cholestyramine and ileal exclusion on cholesterol metabolism. J Lab Clin Med. 1971 Jul;78(1):94–121. [PubMed] [Google Scholar]
  17. Hagenfeldt L., Hellström K. Blood concentration and turnover of circulating mevalonate in the rat. Life Sci II. 1972 Jul 8;11(13):669–676. doi: 10.1016/0024-3205(72)90016-1. [DOI] [PubMed] [Google Scholar]
  18. 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]
  19. Jeske D. J., Dietschy J. M. Regulation of rates of cholesterol synthesis in vivo in the liver and carcass of the rat measured using [3H]water. J Lipid Res. 1980 Mar;21(3):364–376. [PubMed] [Google Scholar]
  20. 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]
  21. 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]
  22. MIETTINEN T. A., AHRENS E. H., Jr, GRUNDY S. M. QUANTITATIVE ISOLATION AND GAS--LIQUID CHROMATOGRAPHIC ANALYSIS OF TOTAL DIETARY AND FECAL NEUTRAL STEROIDS. J Lipid Res. 1965 Jul;6:411–424. [PubMed] [Google Scholar]
  23. McNamara D. J., Ahrens E. H., Jr, Kolb R., Brown C. D., Parker T. S., Davidson N. O., Samuel P., McVie R. M. Treatment of familial hypercholesterolemia by portacaval anastomosis: effect on cholesterol metabolism and pool sizes. Proc Natl Acad Sci U S A. 1983 Jan;80(2):564–568. doi: 10.1073/pnas.80.2.564. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Nikkari T., Schreibman P. H., Ahrens E. H., Jr In vivo studies of sterol and squalene secretion by human skin. J Lipid Res. 1974 Nov;15(6):563–573. [PubMed] [Google Scholar]
  25. Nikkari T., Schreibman P. H., Ahrens E. H., Jr Isotope kinetics of human skin cholesterol secretion. J Exp Med. 1975 Mar 1;141(3):620–634. doi: 10.1084/jem.141.3.620. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. 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]
  27. 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]
  28. 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]
  29. Shapiro D. J., Nordstrom J. L., Mitschelen J. J., Rodwell V. W., Schimke R. T. Micro assay for 3-hydroxy-3-methylglutaryl-CoA reductase in rat liver and in L-cell fibroblasts. Biochim Biophys Acta. 1974 Dec 29;370(2):369–377. doi: 10.1016/0005-2744(74)90098-9. [DOI] [PubMed] [Google Scholar]
  30. Tobert J. A., Bell G. D., Birtwell J., James I., Kukovetz W. R., Pryor J. S., Buntinx A., Holmes I. B., Chao Y. S., Bolognese J. A. Cholesterol-lowering effect of mevinolin, an inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme a reductase, in healthy volunteers. J Clin Invest. 1982 Apr;69(4):913–919. doi: 10.1172/JCI110530. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. 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]

Articles from Journal of Clinical Investigation are provided here courtesy of American Society for Clinical Investigation

RESOURCES