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Abstract: We have investigated comprehensively the effects of thyroid function on gallstone formation in a mouse model. Gonadectomized gallstone-susceptible male c57BL/6 mice were randomly distributed into three groups each of which received an intervention to induce hyperthyroidism, hypothyroidism, or euthyroidism. After 5 weeks of feeding a lithogenic diet of 15% (w/w) butter fat, 1% (w/w) cholesterol, and 0.5% (w/w) cholic acid, mice were killed for further experiments. The incidence of cholesterol monohydrate crystal formation was 100% in mice with hyperthyroidism, 83% in hypothyroidism, and 33% in euthyroidism, the differences being statistically significant. Among the hepatic lithogenic genes, Trβ was found to be up-regulated and Rxr down-regulated in the mice with hypothyroidism. In contrast, Lxrα, Rxr, and Cyp7α1 were up-regulated and Fxr down-regulated in the mice with hyperthyroidism. In conclusion, thyroid dysfunction, either hyperthyroidism or hypothyroidism, promotes the formation of cholesterol gallstones in c57BL/6 mice. Gene expression differences suggest that thyroid hormone disturbance leads to gallstone formation in different ways. hyperthyroidism induces cholesterol gallstone formation by regulating expression of the hepatic nuclear receptor genes such as Lxrα and Rxr, which are significant in cholesterol metabolism pathways. However, hypothyroidism induces cholesterol gallstone formation by promoting cholesterol biosynthesis.

甲状腺功能失调促进胆囊结石形成的机制研究

[1]Admirand, W.H., Small, D.M., 1968. The physicochemical basis of cholesterol gallstone formation in man. J. Clin. Invest., 47(5):1043-1052.

[2]Attili, A.F., Carulli, N., Roda, E., et al., 1995. Epidemiology of gallstone disease in Italy: prevalence data of the multicenter Italian study on cholelithiasis (M.I.COL.). Am. J. Epidemiol., 141(2):158-165.

[3]Attili, A.F., Capocaccia, R., Carulli, N., et al., 1997. Factors associated with gallstone disease in the micol experience. Multicenter Italian study on epidemiology of cholelithiasis. Hepatology, 26(4):809-818.

[4]Bonde, Y., Plosch, T., Kuipers, F., et al., 2012. Stimulation of murine biliary cholesterol secretion by thyroid hormone is dependent on a functional ABCG5/G8 complex. Hepatology, 56(5):1828-1837.

[5]Cakir, M., Kayacetin, E., Toy, H., et al., 2009. Gallbladder motor function in patients with different thyroid hormone status. Exp. Clin. Endocrinol. Diabetes, 117(8):395-399.

[6]Diehl, A.K., 1991. Epidemiology and natural history of gallstone disease. Gastroenterol. Clin. North Am., 20(1):1-19.

[7]Duntas, L.H., 2002. Thyroid disease and lipids. Thyroid, 12(4):287-293.

[8]Galman, C., Bonde, Y., Matasconi, M., et al., 2008. Dramatically increased intestinal absorption of cholesterol following hypophysectomy is normalized by thyroid hormone. Gastroenterology, 134(4):1127-1136.

[9]Germain, P., Chambon, P., Eichele, G., et al., 2006. International union of pharmacology. LXIII. Retinoid X receptors. Pharmacol. Rev., 58(4):760-772.

[10]Gililland, K.R., Finn, D.A., 2007. The impact of gonadectomy and adrenalectomy on acute withdrawal severity in male and female C57BL/6J and DBA/2J mice following a single high dose of ethanol. Alcohol. Clin. Exp. Res., 31(11):1846-1857.

[11]Hashimoto, K., Mori, M., 2011. Crosstalk of thyroid hormone receptor and liver X receptor in lipid metabolism and beyond. Endocr. J., 58(11):921-930.

[12]Hashimoto, K., Yamada, M., Matsumoto, S., et al., 2006. Mouse sterol response element binding protein-1c gene expression is negatively regulated by thyroid hormone. Endocrinology, 147(9):4292-4302.

[13]Hashimoto, K., Matsumoto, S., Yamada, M., et al., 2007. Liver X receptor-α gene expression is positively regulated by thyroid hormone. Endocrinology, 148(10):4667-4675.

[14]Inkinen, J., Sand, J., Arvola, P., et al., 2001. Direct effect of thyroxine on pig sphincter of Oddi contractility. Dig. Dis. Sci., 46(1):182-186.

[15]Khanuja, B., Cheah, Y.C., Hunt, M., et al., 1995. Lith1, a major gene affecting cholesterol gallstone formation among inbred strains of mice. PNAS, 92(17):7729-7733.

[16]Laukkarinen, J., Sand, J., Aittomaki, S., et al., 2002. Mechanism of the prorelaxing effect of thyroxine on the sphincter of Oddi. Scand. J. Gastroenterol., 37(6):667-673.

[17]Laukkarinen, J., Sand, J., Saaristo, R., et al., 2003. Is bile flow reduced in patients with hypothyroidism? Surgery, 133(3):288-293.

[18]Morita, S.Y., Tsuda, T., Horikami, M., et al., 2013. Bile salt-stimulated phospholipid efflux mediated by ABCB4 localized in nonraft membranes. J. Lipid Res., 54(5):1221-1230.

[19]Moschetta, A., Bookout, A.L., Mangelsdorf, D.J., 2004. Prevention of cholesterol gallstone disease by FXR agonists in a mouse model. Nat. Med., 10(12):1352-1358.

[20]Paulusma, C.C., de Waart, D.R., Kunne, C., et al., 2009. Activity of the bile salt export pump (ABCB11) is critically dependent on canalicular membrane cholesterol content. J. Biol. Chem., 284(15):9947-9954.

[21]Pedrelli, M., Pramfalk, C., Parini, P., 2010. Thyroid hormones and thyroid hormone receptors: effects of thyromimetics on reverse cholesterol transport. World J. Gastroenterol., 16(47):5958-5964.

[22]Portincasa, P., Wang, D.Q., 2012. Intestinal absorption, hepatic synthesis, and biliary secretion of cholesterol: where are we for cholesterol gallstone formation? Hepatology, 55(5):1313-1316.

[23]Portincasa, P., Moschetta, A., Palasciano, G., 2006. Cholesterol gallstone disease. Lancet, 368(9531):230-239.

[24]Repa, J.J., Berge, K.E., Pomajzl, C., et al., 2002. Regulation of ATP-binding cassette sterol transporters ABCG5 and ABCG8 by the liver X receptors α and β. J. Biol. Chem., 277(21):18793-18800.

[25]Ros, E., Navarro, S., Bru, C., et al., 1991. Occult microlithiasis in ‘idiopathic’ acute pancreatitis: prevention of relapses by cholecystectomy or ursodeoxycholic acid therapy. Gastroenterology, 101(6):1701-1709.

[26]Tepperman, J., Caldwell, F.T., Tepperman, H.M., 1964. Induction of gallstones in mice by feeding a cholesterol-cholic acid containing diet. Am. J. Physiol., 206:628-634.

[27]van Erpecum, K.J., Wang, D.Q., Lammert, F., et al., 2001. Phenotypic characterization of lith genes that determine susceptibility to cholesterol cholelithiasis in inbred mice: soluble pronucleating proteins in gallbladder and hepatic biles. J. Hepatol., 35(4):444-451.

[28]Vassilakis, J.S., Nicolopoulos, N., 1981. Dissolution of gallstones following thyroxine administration. A case report. Hepatogastroenterology, 28(1):60-61.

[29]Venneman, N.G., van Erpecum, K.J., 2010. Pathogenesis of gallstones. Gastroenterol. Clin. North Am., 39(2):171-183.

[30]Volzke, H., Robinson, D.M., John, U., 2005. Association between thyroid function and gallstone disease. World J. Gastroenterol., 11(35):5530-5534.

[31]Wang, D.Q., Carey, M.C., 1996. Complete mapping of crystallization pathways during cholesterol precipitation from model bile: influence of physical-chemical variables of pathophysiologic relevance and identification of a stable liquid crystalline state in cold, dilute and hydrophilic bile salt-containing systems. J. Lipid Res., 37(3):606-630.

[32]Wang, D.Q., Paigen, B., Carey, M.C., 1997. Phenotypic characterization of lith genes that determine susceptibility to cholesterol cholelithiasis in inbred mice: physical-chemistry of gallbladder bile. J. Lipid Res., 38(7):1395-1411.

[33]Wang, Y., Jiang, Z.Y., Fei, J., et al., 2007. ATP binding cassette G8 T400K polymorphism may affect the risk of gallstone disease among Chinese males. Clin. Chim. Acta, 384(1-2):80-85.