Skip to main content

Advertisement

SpringerLink
Log in

Hepatic cholesterol and bile acid synthesis in Japanese patients with cholesterol gallstones

  • Liver, Pancreas, and Biliary Tract
  • Published:
Gastroenterologia Japonica Aims and scope Submit manuscript

Summary

In Japan the composition of gallstones is changing rapidly from the once-predominant brownpigment stones to cholesterol ones. The present work was undertaken to clarify the mechanism of cholesterol supersaturated bile production in Japanese patients with cholesterol gallstones. In 26 non-obese and normolipidemic patients (11 with cholesterol gallstones, 8 with black- or brown-pigment gallstones, 7 without gallstones) a liver biopsy and hepatic bile were surgically obtained under standardized conditions. The cholesterol saturation of hepatic bile was significantly higher in cholesterol gallstone patients than in gallstone-free controls (195 ±10 vs. 146 ±8%, respectively; P < 0.01). The microsomal activities of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, the rate-limiting enzyme for cholesterol synthesis, cholesterol 7 α-hydroxylase, the rate-limiting enzyme for bile acid synthesis, and 7 α-hydroxy-4-cholesten-3-one 12 α-hydroxylase (12 α-hydroxylase), the rate-limiting enzyme for cholic acid synthesis, were assayed simultaneously in the same subjects. There were positive correlations between HMG-CoA reductase and cholesterol 7 α-hydroxylase activities (Rs = 0.62, P < 0.005), and between cholesterol 7 α-hydroxylase and 12 α-hydroxylase activities (Rs = 0.44, P < 0.05) in all subjects, irrespective of the existence of gallstones. The activities of the three rate-limiting enzymes did not differ significantly among the three groups (cholesterol stone, pigment stone and stone-free). In conclusion, the cholesterol supersaturation of hepatic bile in nonobese and normolipidemic Japanese patients with cholesterol gallstones does not result from an increased hepatic cholesterol synthesis or a decreased bile acid synthesis.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Small DM, Rapo S. Source of abnormal bile in patients with cholesterol gallstones. N Engl J Med 1970;283:53–57.

    Article  PubMed  CAS  Google Scholar 

  2. Vlahcevic ZR, Bell CC Jr, Swell L. Significance of the liver in the production of lithogenic bile in man. Gastroenterology 1970;59: 62–69.

    PubMed  CAS  Google Scholar 

  3. Holan KR, Holzbach RT, Hermann RE, et al. Nucleation time: a key factor in the pathogenesis of cholesterol gallstone disease. Gastroenterology 1979;77:611–617.

    PubMed  CAS  Google Scholar 

  4. Reihnér E, Angelin B, Björkhem I, et al. Hepatic cholesterol metabolism in cholesterol gallstone disease. J Lipid Res 1991;32: 469–475.

    PubMed  Google Scholar 

  5. Redinger RN, Small DM. Bile composition, bile salt metabolism and gallstones. Arch Intern Med 1972;130:618–630.

    Article  PubMed  CAS  Google Scholar 

  6. Nakayama F, van der Linden W. Bile composition: Sweden versus Japan. Am J Surg 1971;122:8–12.

    Article  PubMed  CAS  Google Scholar 

  7. Osuga T, Portman OW, Mitamura K, et al. A morphologic study of gallstone development in the squirrel monkey. Lab Invest 1974;30:486–493.

    PubMed  CAS  Google Scholar 

  8. Osuga T, Mitamura K, Miyagawa S, et al. A scanning electron microscopic study of gallstone development in man. Lab Invest 1974;31:696–704.

    PubMed  CAS  Google Scholar 

  9. Nicolau G, Shefer S, Salen G, et al. Determination of hepatic 3-hydroxy-3-methylglutaryl CoA reductase activity in man. J Lipid Res 1974;15:94–98.

    PubMed  CAS  Google Scholar 

  10. Salen G, Nicolau G, Shefer S, et al. Hepatic cholesterol metabolism in patients with gallstones. Gastroenterology 1975;69:676–684.

    PubMed  CAS  Google Scholar 

  11. Coyne MJ, Bonorris GG, Goldstein LI, et al. Effect of chenodeoxycholic acid and phenobarbital on the rate-limiting enzymes of hepatic cholesterol and bile acid synthesis in patients with gallstones. J Lab Clin Med 1976;87:281–291.

    PubMed  CAS  Google Scholar 

  12. Maton PN, Ellis HJ, Higgins MJP, et al. Hepatic HMGCoA reductase in human cholelithiasis: effects of chenodeoxycholic and ursodeoxycholic acids. Eur J Clin Invest 1980;10:325–332.

    PubMed  CAS  Google Scholar 

  13. Key PH, Bonorris GG, Marks JW, et al. Biliary lipid synthesis and secretion in gallstone patients before and during treatment with chenodeoxycholic acid. J Lab Clin Med 1980;95:816–826.

    PubMed  CAS  Google Scholar 

  14. Nicolau G, Shefer S, Salen G, et al. Determination of hepatic cholesterol 7α-hydroxylase activity in man. J Lipid Res 1974;15:146–151.

    CAS  Google Scholar 

  15. Carulli N, Ponz De Leon M, Zironi F, et al. Hepatic cholesterol and bile acid metabolism in subjects with gallstones: comparative effects of short term feeding of chenodeoxycholic and ursodeoxycholic acid. J Lipid Res 1980;21:35–43.

    PubMed  CAS  Google Scholar 

  16. Kawata S, Imai Y, Inada M, et al. Modulation of cholesterol 7αhydroxylase activity by nonspecific lipid transfer protein in human liver—possibly altered regulation of its cytosolic level in patients with gallstones. Clin Chim Acta 1991;197:201–208.

    Article  PubMed  CAS  Google Scholar 

  17. Honda A, Shoda J, Tanaka N, et al. Simultaneous assay of the activities of two key enzymes in cholesterol metabolism by gas chromatography-mass spectrometry. J Chromatogr 1991;565:53–66.

    Article  PubMed  CAS  Google Scholar 

  18. Angelin B, Backman L, Einarsson K, et al. Hepatic cholesterol metabolism in obesity: activity of microsomal 3-hydroxy-3-methylglutaryl coenzyme A reductase. J Lipid Res 1982;23:770–773.

    PubMed  CAS  Google Scholar 

  19. Kwekkeboom JZ, Kempen HJ, van Voorthuizen EM, et al. Postnatal developmental profile of 3-hydroxy-3-methylglutaryl-CoA reductase, squalene synthetase and cholesterol 7a-hydroxylase activities in the liver of domestic swine. Biochim Biophys Acta 1990;1042:146–149.

    PubMed  CAS  Google Scholar 

  20. Bradford MM. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem 1976;72:248–254.

    Article  PubMed  CAS  Google Scholar 

  21. Noshiro M, Ishida H, Hayashi S, et al. Assays for cholesterol 7ahydroxylase and 12α-hydroxylase using high performance liquid chromatography. Steroids 1985;45:539–549.

    Article  PubMed  CAS  Google Scholar 

  22. Aufenanger J, Kattermann R. Enzymatic determination of lipids in human bile without bilirubin interference: reliable assessment of the cholesterol saturation index (CSI). J Clin Chem Clin Biochem 1989;27:605–611.

    PubMed  CAS  Google Scholar 

  23. Allain CC, Poon LS, Chan CSG, et al. Enzymatic determination of total serum cholesterol. Clin Chem 1974;20:470–475.

    PubMed  CAS  Google Scholar 

  24. Takayama M, Itoh S, Nagasaki T, et al. A new enzymatic method for determination of serum choline-containing phospholipids. Clin Chim Acta 1977;79:93–98.

    Article  PubMed  CAS  Google Scholar 

  25. Mashige F, Tanaka N, Maki A, et al. Direct spectrophotometry of total bile acids in serum. Clin Chem 1981;27:1352–1356.

    PubMed  CAS  Google Scholar 

  26. Carey MC. Critical tables for calculating the cholesterol saturation of native bile. J Lipid Res 1978;19:945–955.

    PubMed  CAS  Google Scholar 

  27. Shoda J, Tanaka N, Matsuzaki Y, et al. Microanalysis of bile acid composition in intrahepatic calculi and its etiological significance Gastroenterology. 1991;101:821–830.

    PubMed  CAS  Google Scholar 

  28. Angelin B, Einarsson K, Liljeqvist L, et al. 3-Hydroxy-3-methylglutaryl coenzyme A reductase in human liver microsomes: active and inactive forms and crossreactivity with antibody against rat liver enzyme. J Lipid Res 1984;25:1159–1166.

    PubMed  CAS  Google Scholar 

  29. Nervi FO, Covarrubias CF, Valdivieso VD, et al. Hepatic cholesterogenesis in Chileans with cholesterol gallstone disease. Gastroenterology 1981;80:539–545.

    PubMed  CAS  Google Scholar 

  30. Ahlberg J, Angelin B, Einarsson K Hepatic 3-hydroxy-3-methylglutaryl coenzyme A reductase activity and biliary lipid composition in man: relation to cholesterol gallstone disease and effects of cholic acid and chenodeoxycholic acid treatment. J Lipid Res 1981;22:410–422.

    PubMed  CAS  Google Scholar 

  31. Oda H, Yamashita H, Kosahara K, et al. Esterified and total 7a-hydroxycholesterol in human serum as an indicator for hepatic bile acid synthesis. J Lipid Res 1990;31:2209–2218.

    PubMed  CAS  Google Scholar 

  32. Shefer S, Hauser S, Lapar V, et al. Regulatory effects of sterols and bile acids on hepatic 3-hydroxy-3-methylglutaryl CoA reductase and cholesterol 7α-hydroxylase in the rat. J Lipid Res 1973;14: 573–580.

    PubMed  CAS  Google Scholar 

  33. Heuman DM, Vlahcevic ZR, Bailey ML, et al. Regulation of bile acid synthesis. II. Effect of bile acid feeding on enzymes regulating hepatic cholesterol and bile acid synthesis in rat. Hepatology 1988;8:892–897.

    Article  PubMed  CAS  Google Scholar 

  34. Vlahcevic ZR, Heuman DM, Hylemon PB. Physiology and pathophysiology of enterohepatic circulation of bile acids. Hepatology. 2nd ed. W.B. Saunders Co., 1990;341-377.

  35. Björkhem I. Mechanism of bile acid biosynthesis in mammalian liver. Sterols and bile acids. Elsevier Science Publishers, 1985;231-278.

  36. Heuman DM, Hylemon PB, Vlahcevic ZR. Regulation of bile acid synthesis. III. Correlation between biliary bile salt hydrophobicity index and the activities of enzymes regulating cholesterol and bile acid synthesis in the rat. J Lipid Res 1989;30:1161–1171.

    PubMed  CAS  Google Scholar 

  37. Reihnér E, Angelin B, Rudling M, et al. Regulation of hepatic cholesterol metabolism in humans: stimulatory effects of cholestyramine on HMG-CoA reductase activity and low density lipoprotein receptor expression in gallstone patients. J Lipid Res 1990; 31:2219–2226.

    PubMed  Google Scholar 

  38. Carey MC, Small DM. The physical chemistry of cholesterol solubility in bile. J Clin Invest 1978;61:998–1026.

    PubMed  CAS  Google Scholar 

  39. Heaton KW, Read AE. Gallstones in patients with disorders of the terminal ileum and disturbed bile salt metabolism. Br Med J 1969;30:494–496.

    Article  Google Scholar 

  40. Ahlberg J, Angelin B, Einarsson K, et al. Biliary lipid composition in normo- and hyperlipoproteinemia. Gastroenterology 1980;79: 90–94.

    PubMed  CAS  Google Scholar 

  41. Bennion LJ, Grundy SM. Effects of diabetes mellitus on cholesterol metabolism in man. N Engl J Med 1977;296:1365–1371.

    Article  PubMed  CAS  Google Scholar 

  42. Stone BG, Evans CD, Fadden RJ, et al. Regulation of hepatic cholesterol ester hydrolase and acyl-coenzyme A: cholesterol acyltransferase. J Lipid Res 1989;30:1681–1690.

    PubMed  CAS  Google Scholar 

  43. Ochoa B, Gee A, Jackson B, et al. Regulation of cholesteryl ester metabolism in the hamster liver. Biochim Biophys Acta 1990; 1044:133–138.

    PubMed  CAS  Google Scholar 

  44. Smith JL, Hardie IR, Pillay SP, et al. Hepatic acyl-coenzyme A: cholesterol acyltransferase activity is decreased in patients with cholesterol gallstones. J Lipid Res 1990;31:1993–2000.

    PubMed  CAS  Google Scholar 

  45. Robins SJ, Fasulo JM, Collins MA, et al. Evidence for separate pathways of transport of newly synthesized and preformed cholesterol into bile. J Biol Chem 1985;260:6511–6513.

    PubMed  CAS  Google Scholar 

  46. Mitchell JC, Stone BG, Logan GM, et al. Role of cholesterol synthesis in regulation of bile acid synthesis and biliary cholesterol secretion in humans. J Lipid Res 1991;32:1143–1149.

    PubMed  CAS  Google Scholar 

  47. Vlahcevic ZR, Bell CC Jr, Buhac I, et al. Diminished bile acid pool size in patients with gallstones. Gastroenterology 1970;59:165–173.

    PubMed  CAS  Google Scholar 

  48. Swell L, Bell CC Jr, Vlahcevic ZR Relationship of bile acid pool size to biliary lipid excretion and the formation of lithogenic bile in man. Gastroenterology 1971;61:716–722.

    PubMed  CAS  Google Scholar 

  49. Pomare EW, Heaton KW. Bile salt metabolism in patients with gallstones in functioning gallbladders. Gut 1973;14:885–890.

    Article  PubMed  CAS  Google Scholar 

  50. Shaffer EA, Small DM. Biliary lipid secretion in cholesterol gallstone disease. J Clin Invest 1977;59:828–840.

    PubMed  CAS  Google Scholar 

  51. Onuki M, Saito H, Hatta Y. The kinetics of bile acids in patients with cholesterol gallstones. Jpn J Gastroenterol 1982;79:956–963. (in Japanese)

    CAS  Google Scholar 

  52. Nilsell K, Angelin B, Liljeqvist L, et al. Biliary lipid output and bile acid kinetics in cholesterol gallstone disease. Gastroenterology 1985;89:287–293.

    PubMed  CAS  Google Scholar 

  53. Bell CC Jr, Vlahcevic ZR. Evidence that a diminished bile acid pool precedes the formation of cholesterol gallstones in man. Surg Gynecol Obstet 1973;136:961–965.

    PubMed  Google Scholar 

  54. Lindstedt S: The turnover of cholic acid in man. Acta Physiol Scand 1957;40:1–9.

    PubMed  Google Scholar 

  55. Vlahcevic ZR, Miller JR, Farrar JT, et al. Kinetics and pool size of primary bile acids in man. Gastroenterology 1971;61:85–90.

    PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Gastroenterology, Institute of Clinical Medicine, University of Tsukuba, Ibaraki, Japan

    Akira Honda, Tadashi Yoshida, Naomi Tanaka, Yasushi Matsuzaki, Bingfang He & Toshiaki Osuga M.D.

  2. First Department of Surgery, Ehime University School of Medicine, Ehime, Japan

    Nobuaki Kobayashi

  3. Second Department of Surgery, Faculty of Medicine, Kyoto University, Kyoto, Japan

    Kazue Ozawa

Authors
  1. Akira Honda
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Tadashi Yoshida
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Naomi Tanaka
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yasushi Matsuzaki
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Bingfang He
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Toshiaki Osuga M.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Nobuaki Kobayashi
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Kazue Ozawa
    View author publications

    You can also search for this author in PubMed Google Scholar

Additional information

This study was supported in part by a Grant-in-Aid for Scientific Research (No. 02454226) from the Ministry of Education, Science and Culture of Japan, and a grant from University of Tsukuba Project Research.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Honda, A., Yoshida, T., Tanaka, N. et al. Hepatic cholesterol and bile acid synthesis in Japanese patients with cholesterol gallstones. Gastroenterol Jpn 28, 406–414 (1993). https://doi.org/10.1007/BF02776986

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF02776986

Key words

Search

Navigation