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Lithogenic diet and gallstone formation in mice: integrated response of activities of regulatory enzymes in hepatic cholesterol metabolism

Published online by Cambridge University Press:  09 March 2007

Eva Reihnér  and
Dagny Ståhlberg
Eva Reihnér
Affiliation:
Department of Surgery, Karolinska Institutet, Huddinge University Hospital, S-141 86 Huddinge, Sweden
Dagny Ståhlberg
Affiliation:
Department of Medicine, Karolinska Institutet, Huddinge University Hospital, S-141 86 Huddinge, Sweden
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Abstract

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Supersaturation of bile with cholesterol is a prerequisite of the development of gallstones. With the intention to study the integrated response of enzymes regulating hepatic cholesterol metabolism during gallstone formation we used an established model for the induction of cholesterol gallstone disease in mice. Ten mice were fed on a lithogenic diet containing 10 g cholesterol/kg and 5 g cholic acid/kg for 8 weeks and were compared with ten mice fed on a standard pellet diet. Cholesterol crystals or gallstones developed in 90% of gallbladders in treated mice. The lithogenic diet had an inhibitory effect on the rate-limiting enzyme of cholesterol biosynthesis, hepatic 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase (EC 1.1.1.88) activity, 39·6 (SEM 2·8) v. 171·0 (SEM 47·3) pmol/min per mg protein. Cholesterol 7α-hydroxylase (EC 1.14.13.17) activity, regulating bile acid synthesis, was decreased by 80%, and this was assumed to be due to cholic acid in the diet. The cholesterol-enriched diet also induced a tenfold increase in cholesterol esterification rate in the liver, i.e. acyl-CoA: cholesterol acyl transferase (ACAT; EC 2.3.1.26) activity. The total, as well as esterified, cholesterol contents of liver homogenates were significantly higher in cholesterol- and cholic acid-treated mice and correlated well with the ACAT activity (rs 0·72 (P < 0·005), and rs 0·68 (P < 0·01) respectively). A significantly higher ACAT activity was obtained in mice given cholesterol and cholic acid even when the enzyme was saturated with exogenous cholesterol, thus indicating an increased amount of the enzyme. The formation of gallstones is dependent on a delicate balance between lithogenic factors (increased absorption of cholesterol and reduced secretion of bile acids) and defence mechanisms (decreased synthesis and increased esterification of cholesterol). In the specific animal model studied here the two defence mechanisms cannot compensate for the increased absorption of cholesterol and the reduced synthesis of bile acids.

Keywords

Lithogenic dietHepatic cholesterol metabolismGallstones
Type
General Nutrition
Information
British Journal of Nutrition , Volume 76 , Issue 5 , November 1996 , pp. 765 - 772
Copyright
Copyright © The Nutrition Society 1996

References

REFERENCES

Admirand, W. H. & Small, D. M. (1968). The physicochemical basis of cholesterol gallstone formation in man. Journal of Clinical Investigation 47, 1043–1052.CrossRefGoogle ScholarPubMed
Angelin, B., Einarsson, K., Liljeqvist, L., Nilsell, K. & Heller, R. A. (1984). 3-Hydroxy-3-methylglutaryl coenzyme A reductase in human liver microsomes: active and inactive forms and cross-reactivity with antibody against rat liver enzyme. Journal of Lipid Research 25, 1159–1166.CrossRefGoogle Scholar
Bergman, F., Juul, A. H. & van der Linden, W. (1970). Development and regression of morphological and biochemical changes in hamsters and mice fed a cholesterol cholic acid containing diet. Acta Pathologica et Microbiologica Scandinavica 78, 179–191.Google ScholarPubMed
Björkhem, I. & Kallner, A. (1976). Hepatic 7 α-hydroxylation of cholesterol in ascorbate deficient and ascorbate-supplemented guinea pigs. Journal of Lipid Research 17, 360–365.CrossRefGoogle Scholar
Caldwell, F. T., Levitsky, K. & Rosenberg, B. (1965). Dietary production and dissolution of cholesterol gallstones in the mouse. American Journal of Physiology 209, 473–478.CrossRefGoogle ScholarPubMed
Dueland, S., Drisko, J., Graf, L., Machleder, D., Lusis, A. J. & Davis, R. A. (1993). Effect of dietary cholesterol and taurocholate on cholesterol 7 α-hydroxylase and hepatic LDL receptors in inbred mice. Journal of Lipid Research 34, 923–931.CrossRefGoogle ScholarPubMed
Einarsson, K., Angelin, B., Ewerth, S., Nilsell, K. & Bjorkhem, I. (1986). Bile acid synthesis in man: assay of hepatic microsomal cholesterol 7 α-hydroxylase activity by isotope dilution-mass spectrometry. Journal of Lipid Research 27, 82–88.CrossRefGoogle ScholarPubMed
Einarsson, K., Benthin, L., Ewerth, S., Hellers, G., Stihlberg, D. & Angelin, B. (1989). Studies on acyl-coenzyme A: cholesterol acyltransferase activity in human liver microsomes. Journal of Lipid Research 30, 739–746.CrossRefGoogle ScholarPubMed
Heuman, D. M., Vlahcevic, Z. R., Bailey, M. L. & Hylemon, P. B. (1988). Regulation of bile acid synthesis. II. Effect of bile acid feeding on enzymes regulating hepatic cholesterol and bile acid synthesis in the rat. Hepatology 8, 892–897.CrossRefGoogle ScholarPubMed
Holzbach, R. T. (1984). Animal models of cholesterol gallstone disease. Hepatology 4, 191S–198S.CrossRefGoogle ScholarPubMed
Lowry, O. H., Rosebrough, N. J., Farr, A. L. & Randall, R. J. (1951). Protein measurement with the Folin phenol reagent. Journal of Biological Chemistry 193, 265–275.CrossRefGoogle ScholarPubMed
Nakamura-Yamanaka, Y., Tsuji, K. & Ichikawa, T. (1987). Effect of dietary taurine on cholesterol 7 α-hydroxylase activity in the liver of mice fed a lithogenic diet. Journal of Nutritional Science and Vitaminology 33, 239–243.CrossRefGoogle ScholarPubMed
Nervi, F., Bronfman, M., Allalo'n, W., Depiereux, E. & Del Pozo, R. (1984). Regulation of biliary cholesterol secretion in the rat. Role of hepatic cholesterol esterification. Journal of Clinical Investigation 74, 2226–2237.CrossRefGoogle ScholarPubMed
Pape, M. E., Schultz, P. A., Rea, T. J., De Mattos, R. B., Kieft, K., Bisgaier, C. L., Newton, R. S. & Krause, B. R. (1995). Tissue specific changes in acyl-CoA: cholesterol acyltransferase (ACAT) mRNA levels in rabbits. Journal of Lipid Research 36, 823–838.CrossRefGoogle ScholarPubMed
Rege, R. V. & Ostrow, J. D. (1995). Animal models of pigment and cholesterol gallstone disease. In Methods in Biliary Research, pp 203–243 [Muraca, M., editor]. Boca Raton, FL: CRC Press.Google Scholar
Reynier, M. O., Montet, J. C., Gerolami, A., Marteau, C., Crotte, C., Montet, A. M. & Mathieu, S. (1981). Comparative effects of cholic, chenodeoxycholic, and ursodeoxycholic acids on micellar solubilization and intestinal absorption of cholesterol. Journal of Lipid Research 22, 467–473.CrossRefGoogle ScholarPubMed
Rudling, M. (1992). Hepatic mRNA levels of the LDL receptor and HMG-CoA reductase show coordinate regulation in vivo. Journal of Lipid Research 33, 493–501.CrossRefGoogle ScholarPubMed
Schaffer, R., Sniegoski, L. T., Welch, M. J., White, V. A., Cohen, H. S., Hertz, J., Mandel, R. C., Paule, L., Svensson, L., Bjorkhem, I. & Blomstrand, R. (1982). Comparison of two isotope dilution mass spectrometric methods for determination of total serum cholesterol. Clinical Chemistry 28, 5–8.CrossRefGoogle ScholarPubMed
Shefer, S., Hauser, S., Lapar, V. & Mosbach, E. H. (1973). Regulatory effects of sterols and bile acids on hepatic 3-hydroxy-3-methylglutaryl CoA reductase and cholesterol 7 α-hydroxylase in the rat. Journal of Lipid Research 14, 573–580.CrossRefGoogle Scholar
Spady, D. K. & Cuthbert, A. (1992). Regulation of hepatic sterol metabolism in the rat. Parallel regulation of activity and mRNA for 7 α-hydroxylase but not 3-hydroxy-3-methylglutaryl coenzyme A reductase or low density lipoprotein receptor. Journal of Biological Chemistry 267, 5584–5591.CrossRefGoogle ScholarPubMed
Stone, B. G., Erickson, S. K., Craig, W. Y. & Cooper, A. D. (1985). Regulation of rat biliary cholesterol secretion by agents that alter intrahepatic cholesterol metabolism. Evidence for a distinct biliary precursor pool. Journal of Clinical Investigation 76, 1773–1781.CrossRefGoogle ScholarPubMed
Suckling, K. E. & Stange, E. F. (1985). Role of acyl-CoA:cholesterol acyltransferase in cellular cholesterol metabolism. Journal of Lipid Research 26, 647–671.CrossRefGoogle ScholarPubMed
Tepperman, J., Caldwell, F. T. & Tepperman, H. M. (1964). Induction of gallstones in mice by feeding a cholesterol-cholic acid containing diet. American Journal of Physiology 206, 628–640.CrossRefGoogle ScholarPubMed
Turley, S. D. & Dietschy, J. M. (1988). The metabolism and excretion of cholesterol by the liver. In The Liver: Biology and Pathobiology 2nd ed., pp. 617–641 [Arias, I. M., Jakoby, W. B., Popper, H., Schachter, D. & Shafritz, D. A., editors]. New York: Raven Press.Google Scholar
Uchida, K., Akiyoshi, T., Igimi, H., Takas, H., Nomura, Y. & Ishihara, S. (1991). Differential effects of ursodeoxycholic acid and ursocholic acid on the formation of biliary cholesterol crystals in mice. Lipids 26, 526–530.CrossRefGoogle ScholarPubMed
Whiting, M. J. & Watts, J. McK. (1987). Role of cholic acid in the dietary induction of cholesterol gall-bladder stones in mice. Journal of Gastroenterology and Hepatology 2, 547–555.Google Scholar
Yamanaka, Y., Tsuji, K. & Ichikawa, T. (1986). Simulation of chenodeoxycholic acid excretion in hypercholesterolemic mice by dietary taurine. Journal of Nutritional Science and Vitaminology 32, 287–296.CrossRefGoogle Scholar
Yellin, T. O., Klaiber, M. S. & Webb, E. (1973). Lithogenic effects of cholic acid and chenodeoxycholic acid in the cholesterol fed mouse. Biochimica et Biophysica Acta 320, 478–485.CrossRefGoogle ScholarPubMed