Skip to main content
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1993 Aug;92(2):911–918. doi: 10.1172/JCI116666

Effects of lovastatin and dietary cholesterol on sterol homeostasis in healthy human subjects.

W C Duane 1
PMCID: PMC294930  PMID: 8349825

Abstract

We measured biliary and fecal sterol outputs in 12 human subjects on a metabolic ward in four randomly allocated, 6-7 wk periods: (a) lovastatin (40 mg b.i.d.) + low cholesterol diet (mean 246 mg/d), (b) lovastatin + high cholesterol diet (mean 1,071 mg/d), (c) low cholesterol diet alone, (d) high cholesterol diet alone. In addition to lowering serum LDL cholesterol, lovastatin significantly lowered biliary secretion of cholesterol, fecal output of endogenous neutral sterols, cholesterol balance, and systemic cholesterol input (the sum of cholesterol synthesis and absorbed dietary cholesterol). The high cholesterol diet significantly lowered cholesterol balance, but significantly increased systemic cholesterol input and fecal output of acidic sterols. There was no significant interaction between lovastatin and dietary cholesterol for any parameter measured. Judging from these data, the primary action of lovastatin is to lower cholesterol synthesis and systemic cholesterol input, the main compensatory response being reduced biliary cholesterol secretion. Conversely, increased dietary cholesterol appears to increase systemic cholesterol input, the major compensatory response being increased bile acid synthesis. There appears to be no interaction between these two perturbations of systemic cholesterol input.

Full text

PDF
918

Selected References

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

  1. Allain C. C., Poon L. S., Chan C. S., Richmond W., Fu P. C. Enzymatic determination of total serum cholesterol. Clin Chem. 1974 Apr;20(4):470–475. [PubMed] [Google Scholar]
  2. Applebaum-Bowden D., Haffner S. M., Hartsook E., Luk K. H., Albers J. J., Hazzard W. R. Down-regulation of the low-density lipoprotein receptor by dietary cholesterol. Am J Clin Nutr. 1984 Mar;39(3):360–367. doi: 10.1093/ajcn/39.3.360. [DOI] [PubMed] [Google Scholar]
  3. Bates M. C., Warren S. G., Grubb S., Chillag S. Effectiveness of low-dose lovastatin in lowering serum cholesterol. Experience with 56 patients. Arch Intern Med. 1990 Sep;150(9):1947–1950. [PubMed] [Google Scholar]
  4. Bradford R. H., Shear C. L., Chremos A. N., Franklin F. A., Nash D. T., Hurley D. P., Dujovne C. A., Pool J. L., Schnaper H., Hesney M. Expanded clinical evaluation of lovastatin (EXCEL) study results: III. Efficacy in modifying lipoproteins and implications for managing patients with moderate hypercholesterolemia. Am J Med. 1991 Jul 31;91(1B):18S–24S. doi: 10.1016/0002-9343(91)90052-y. [DOI] [PubMed] [Google Scholar]
  5. Cobb M. M., Teitelbaum H. S., Breslow J. L. Lovastatin efficacy in reducing low-density lipoprotein cholesterol levels on high- vs low-fat diets. JAMA. 1991 Feb 27;265(8):997–1001. [PubMed] [Google Scholar]
  6. DenBesten L., Connor W. E., Bell S. The effect of dietary cholesterol on the composition of human bile. Surgery. 1973 Feb;73(2):266–273. [PubMed] [Google Scholar]
  7. Duane W. C., Hunninghake D. B., Freeman M. L., Pooler P. A., Schlasner L. A., Gebhard R. L. Simvastatin, a competitive inhibitor of HMG-CoA reductase, lowers cholesterol saturation index of gallbladder bile. Hepatology. 1988 Sep-Oct;8(5):1147–1150. doi: 10.1002/hep.1840080531. [DOI] [PubMed] [Google Scholar]
  8. Duane W. C., Hutton S. W. Lack of effect of experimental ascorbic acid deficiency on bile acid metabolism, sterol balance, and biliary lipid composition in man. J Lipid Res. 1983 Sep;24(9):1186–1195. [PubMed] [Google Scholar]
  9. Duane W. C. Simulation of the defect of bile acid metabolism associated with cholesterol cholelithiasis by sorbitol ingestion in man. J Lab Clin Med. 1978 Jun;91(6):969–978. [PubMed] [Google Scholar]
  10. Everson G. T., McKinley C., Kern F., Jr Mechanisms of gallstone formation in women. Effects of exogenous estrogen (Premarin) and dietary cholesterol on hepatic lipid metabolism. J Clin Invest. 1991 Jan;87(1):237–246. doi: 10.1172/JCI114977. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Freeman M. L., Prigge W. F., Hunninghake D. B., Duane W. C., Gebhard R. L. Intestinal HMG-CoA reductase activity is low in hypercholesterolemic patients and is further decreased with lovastatin therapy. J Lipid Res. 1988 Jul;29(7):839–845. [PubMed] [Google Scholar]
  12. Goldberg I. J., Holleran S., Ramakrishnan R., Adams M., Palmer R. H., Dell R. B., Goodman D. S. Lack of effect of lovastatin therapy on the parameters of whole-body cholesterol metabolism. J Clin Invest. 1990 Sep;86(3):801–808. doi: 10.1172/JCI114777. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Goodman D. S., Smith F. R., Seplowitz A. H., Ramakrishnan R., Dell R. B. Prediction of the parameters of whole body cholesterol metabolism in humans. J Lipid Res. 1980 Aug;21(6):699–713. [PubMed] [Google Scholar]
  14. Grundy S. M., Bilheimer D. W. Inhibition of 3-hydroxy-3-methylglutaryl-CoA reductase by mevinolin in familial hypercholesterolemia heterozygotes: effects on cholesterol balance. Proc Natl Acad Sci U S A. 1984 Apr;81(8):2538–2542. doi: 10.1073/pnas.81.8.2538. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Grundy S. M., Metzger A. L. A physiological method for estimation of hepatic secretion of biliary lipids in man. Gastroenterology. 1972 Jun;62(6):1200–1217. [PubMed] [Google Scholar]
  16. Grundy S. M., Mok H. Y. Determination of cholesterol absorption in man by intestinal perfusion. J Lipid Res. 1977 Mar;18(2):263–271. [PubMed] [Google Scholar]
  17. Grundy S. M., Vega G. L. Influence of mevinolin on metabolism of low density lipoproteins in primary moderate hypercholesterolemia. J Lipid Res. 1985 Dec;26(12):1464–1475. [PubMed] [Google Scholar]
  18. Gylling H., Miettinen T. A. Cholesterol absorption and synthesis related to low density lipoprotein metabolism during varying cholesterol intake in men with different apoE phenotypes. J Lipid Res. 1992 Sep;33(9):1361–1371. [PubMed] [Google Scholar]
  19. Hegsted D. M. Serum-cholesterol response to dietary cholesterol: a re-evaluation. Am J Clin Nutr. 1986 Aug;44(2):299–305. doi: 10.1093/ajcn/44.2.299. [DOI] [PubMed] [Google Scholar]
  20. Hoogerbrugge-vd Linden N., de Rooy F. W., Jansen H., van Blankenstein M. Effect of pravastatin on biliary lipid composition and bile acid synthesis in familial hypercholesterolaemia. Gut. 1990 Mar;31(3):348–350. doi: 10.1136/gut.31.3.348. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Ishida F., Sato A., Iizuka Y., Sawasaki Y., Aizawa A., Kamei T. Effects of MK-733, an inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A reductase, on absorption and excretion of [3H]cholesterol in rabbits. Biochim Biophys Acta. 1988 Nov 4;963(1):35–41. doi: 10.1016/0005-2760(88)90335-9. [DOI] [PubMed] [Google Scholar]
  22. Ishida F., Watanabe K., Sato A., Taguchi K., Kakubari K., Kitani K., Kamei T. Comparative effects of simvastatin (MK-733) and pravastatin (CS-514) on hypercholesterolemia induced by cholesterol feeding in rabbits. Biochim Biophys Acta. 1990 Feb 23;1042(3):365–373. doi: 10.1016/0005-2760(90)90166-u. [DOI] [PubMed] [Google Scholar]
  23. Kern F., Jr Normal plasma cholesterol in an 88-year-old man who eats 25 eggs a day. Mechanisms of adaptation. N Engl J Med. 1991 Mar 28;324(13):896–899. doi: 10.1056/NEJM199103283241306. [DOI] [PubMed] [Google Scholar]
  24. Keys A. Serum cholesterol response to dietary cholesterol. Am J Clin Nutr. 1984 Aug;40(2):351–359. doi: 10.1093/ajcn/40.2.351. [DOI] [PubMed] [Google Scholar]
  25. Lin D. S., Connor W. E. The long term effects of dietary cholesterol upon the plasma lipids, lipoproteins, cholesterol absorption, and the sterol balance in man: the demonstration of feedback inhibition of cholesterol biosynthesis and increased bile acid excretion. J Lipid Res. 1980 Nov;21(8):1042–1052. [PubMed] [Google Scholar]
  26. 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]
  27. Mazzella G., Parini P., Festi D., Bazzoli F., Aldini R., Roda A., Tonelli D., Cipolla A., Salzetta A., Roda E. Effect of simvastatin, ursodeoxycholic acid and simvastatin plus ursodeoxycholic acid on biliary lipid secretion and cholic acid kinetics in nonfamilial hypercholesterolemia. Hepatology. 1992 Jun;15(6):1072–1078. doi: 10.1002/hep.1840150617. [DOI] [PubMed] [Google Scholar]
  28. McGowan M. W., Artiss J. D., Strandbergh D. R., Zak B. A peroxidase-coupled method for the colorimetric determination of serum triglycerides. Clin Chem. 1983 Mar;29(3):538–542. [PubMed] [Google Scholar]
  29. McMurry M. P., Connor W. E., Lin D. S., Cerqueira M. T., Connor S. L. The absorption of cholesterol and the sterol balance in the Tarahumara Indians of Mexico fed cholesterol-free and high cholesterol diets. Am J Clin Nutr. 1985 Jun;41(6):1289–1298. doi: 10.1093/ajcn/41.6.1289. [DOI] [PubMed] [Google Scholar]
  30. McNamara D. J., Kolb R., Parker T. S., Batwin H., Samuel P., Brown C. D., Ahrens E. H., Jr Heterogeneity of cholesterol homeostasis in man. Response to changes in dietary fat quality and cholesterol quantity. J Clin Invest. 1987 Jun;79(6):1729–1739. doi: 10.1172/JCI113013. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Miettinen T. A. Inhibition of cholesterol absorption by HMG-CoA reductase inhibitor. Eur J Clin Pharmacol. 1991;40 (Suppl 1):S19–S21. [PubMed] [Google Scholar]
  32. Mistry P., Miller N. E., Laker M., Hazzard W. R., Lewis B. Individual variation in the effects of dietary cholesterol on plasma lipoproteins and cellular cholesterol homeostasis in man. Studies of low density lipoprotein receptor activity and 3-hydroxy-3-methylglutaryl coenzyme A reductase activity in blood mononuclear cells. J Clin Invest. 1981 Feb;67(2):493–502. doi: 10.1172/JCI110058. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Mitchell J. C., Logan G. M., Stone B. G., Duane W. C. Effects of lovastatin on biliary lipid secretion and bile acid metabolism in humans. J Lipid Res. 1991 Jan;32(1):71–78. [PubMed] [Google Scholar]
  34. Mitchell J. C., Stone B. G., Logan G. M., Duane W. C. Role of cholesterol synthesis in regulation of bile acid synthesis and biliary cholesterol secretion in humans. J Lipid Res. 1991 Jul;32(7):1143–1149. [PubMed] [Google Scholar]
  35. Nestel P. J., Poyser A. Changes in cholesterol synthesis and excretion when cholesterol intake is increased. Metabolism. 1976 Dec;25(12):1591–1599. doi: 10.1016/0026-0495(76)90112-8. [DOI] [PubMed] [Google Scholar]
  36. Packard C. J., McKinney L., Carr K., Shepherd J. Cholesterol feeding increases low density lipoprotein synthesis. J Clin Invest. 1983 Jul;72(1):45–51. doi: 10.1172/JCI110983. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Quintão E., Grundy S. M., Ahrens E. H., Jr Effects of dietary cholesterol on the regulation of total body cholesterol in man. J Lipid Res. 1971 Mar;12(2):233–247. [PubMed] [Google Scholar]
  38. Reihnér E., Rudling M., Ståhlberg D., Berglund L., Ewerth S., Björkhem I., Einarsson K., Angelin B. Influence of pravastatin, a specific inhibitor of HMG-CoA reductase, on hepatic metabolism of cholesterol. N Engl J Med. 1990 Jul 26;323(4):224–228. doi: 10.1056/NEJM199007263230403. [DOI] [PubMed] [Google Scholar]
  39. Smit J. W., van Erpecum K. J., Stolk M. F., Geerdink R. A., Cluysenaer O. J., Erkelens D. W., van Berge Henegouwen G. P. Successful dissolution of cholesterol gallstone during treatment with pravastatin. Gastroenterology. 1992 Sep;103(3):1068–1070. doi: 10.1016/0016-5085(92)90045-z. [DOI] [PubMed] [Google Scholar]
  40. Vanhanen H., Kesäniemi Y. A., Miettinen T. A. Pravastatin lowers serum cholesterol, cholesterol-precursor sterols, fecal steroids, and cholesterol absorption in man. Metabolism. 1992 Jun;41(6):588–595. doi: 10.1016/0026-0495(92)90050-k. [DOI] [PubMed] [Google Scholar]

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

RESOURCES