Effect of -muricholic acid on the prevention and dissolution of cholesterol gallstones in C57L/J mice

This study investigated whether -muricholic acid, a natural trihydroxy hydrophilic bile acid of rodents, acts as a biliary cholesterol-desaturating agent to prevent cholesterol gallstones and if it facilitates the dissolution of gallstones compared with ursodeoxycholic acid (UDCA). For gallstone prevention study, gallstone-susceptible male C57L mice were fed 8 weeks with a lithogenic diet (2% cholesterol and 0.5% cholic acid) with or without 0.5% UDCA or -muricholic acid. For gallstone dissolution study, additional groups of mice that have formed gallstones were fed chow with or without 0.5% -muricholic acid or UDCA for 8 weeks. One hundred percent of mice fed the lithogenic diet formed cholesterol gallstones. Addition of -muricholic acid and UDCA decreased gallstone prevalence to 20% and 50% through significantly reducing biliary secretion rate, saturation index, and intestinal absorption of cholesterol, as well as inducing phase boundary shift and an enlarged Region E that prevented the transition of cholesterol from its liquid crystalline phase to solid crystals and stones. Eight weeks of -muricholic acid and UDCA administration produced complete gallstone dissolution rates of 100% and 60% compared with the chow (10%). We conclude that -muricholic acid is more effective than UDCA in treating or preventing dietinduced or experimental cholesterol gallstones in mice. —Wang, D. Q-H., and S. Tazuma. Effect of -muricholic acid on the prevention and dissolution of cholesterol gallstones in C57L/J mice. J. Lipid Res. 2002. 43: 1960–1968. Supplementary key words bile flow • phospholipid • intestinal cholesterol absorption • phase diagram Cholesterol gallstones are a major public health problem in all developed countries. In the United States, approximately 10–15% of the adult population suffers from cholesterol gallstones (1, 2), which constitutes one of the most common and most costly digestive diseases (3). Long-term administration of ursodeoxycholic acid (UDCA), a hydrophilic bile acid, has been shown to promote the dissolution of cholesterol gallstones (4) and to prevent the recurrence of gallstones after extracorporeal shock wave lithotripsy (5). Therapeutic mechanisms of UDCA include decreasing biliary secretion and intestinal absorption of cholesterol (6, 7), both of which could contribute to a decrease in bile cholesterol saturation. However, UDCA constitutes only 50% of the biliary bile acid pool in patients with cholesterol gallstones (8, 9). The human intestinal bacteria can transform UDCA to lithocholic acid (10, 11) that is shown to be a hepatotoxic bile acid to laboratory animals (12). -muricholic acid (3 ,6 ,7 -trihydroxy-5 -cholan-24-oic acid) is a natural trihydroxy hydrophilic bile acid, which is a major bile acid biosynthesized by rat (13) and mouse (14) liver and found in their bile. Because of the presence of a hydroxy group in the 6 position of the steroid ring, -muricholic acid (15) is more hydrophilic than UDCA. In vitro studies (15) have demonstrated that -muricholic acid can dissolve solid cholesterol monohydrate crystals via formation of a liquid crystalline mesophase, suggesting that it may be used to dissolve cholesterol gallstones. However, Cohen et al. (16) found that feeding low (0.1%) dose of -muricholic acid for 6 weeks does not dissolve preexisting gallstones in prairie dogs or hamsters. Moreover, feeding 0.1% -muricholic acid inhibits gallstone formation in hamsters, but fails to prevent gallstone formation in prairie dogs (16). Therefore, in this study we compared physical-chemical properties of -muricholic acid with UDCA and investigated i ) whether -muricholic acid acts as a poAbbreviations: CSI, cholesterol saturation index; HPLC, high performance liquid chromatography; UDCA, ursodeoxycholic acid. 1 This paper was presented in part at the Annual Meeting of the American Gastroenterological Association, Atlanta, GA, and published as an abstract in Gastroenterology. 2001. 120: A205. 2 To whom correspondence should be addressed. e-mail: [email protected] Manuscript received 26 July 2002. Published, JLR Papers in Press, August 16, 2002. DOI 10.1194/jlr.M200297-JLR200 by gest, on N ovem er 7, 2017 w w w .j.org D ow nladed fom