Cholesterol gallstones are more common in women than men in every population that has been studied. This difference between women and men begins during puberty and continues through the childbearing years, focusing attention upon the effects of female sex hormones. The increased risk of cholesterol gallstones in women vs. men is related to differences in how the liver metabolizes cholesterol in response to estrogen. We employed quantitative trait locus (QTL) analyses of an intercross between inbred strains AKR/J and A/J to determine the subset of gallstone susceptibility genes these strains possess. Significantly, a new QTL is detected and named Lith5 that is mapped to mouse chromosome 10. Our molecular and genetic data support the candidacy of the ER_z gene, encoding estrogen receptor o_, as a major gene underlying Lith5, as well as the hepatic ERa, but not ER[3, plays a critical role in 17[3-estradiol (E2)-induced gallstones. However, the identification of lithogenic effects of Lith5 remains a significant challenge. This renewal application is focused on identifying the lithogenic effects of Lith5 by systematically studying its pathophysiological and biochemical functions in some """"""""manufactured"""""""" mouse strains such as ERo_ (-/-), ATP-binding cassette transporters GS/G8 (ABCG5/G8) (-/-), and cholecystokinin-1 receptor (CCK-1R) (-/-) mice. The applicant proposes to (i) investigate whether targeted disruption of the murine Lith5/Era gene decreases susceptibility to cholesterol gallstone formation; (ii) test the hypothesis that E2-Lith5/ERo_-ABCG5/G8 pathway is responsible for biliary cholesterol hypersecretion; (iii) determine the alterations induced by Lith5_Rc_ in hepatic cholesterol and bile salt metabolism that account for cholesterol supersaturated bile; and (iv) explore whether E2-Lith5/ERa-CCK-1R pathway induces gallbladder hypomotility during cholesterol gallstone formation. This work should pave the way for identifying the major Lith genes in humans, which, in turn, should lead to strategies for early diagnosis of the trait and rational approaches to prevention.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
Project #
Application #
Study Section
Hepatobiliary Pathophysiology Study Section (HBPP)
Program Officer
Serrano, Jose
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Beth Israel Deaconess Medical Center
United States
Zip Code
Wang, David Q-H; Carey, Martin C (2014) Therapeutic uses of animal biles in traditional Chinese medicine: an ethnopharmacological, biophysical chemical and medicinal review. World J Gastroenterol 20:9952-75
Di Ciaula, Agostino; Wang, David Q-H; Garruti, Gabriella et al. (2014) Therapeutic reflections in cholesterol homeostasis and gallstone disease: a review. Curr Med Chem 21:1435-47
Grattagliano, Ignazio; de Bari, Ornella; Bernardo, Telma C et al. (2012) Role of mitochondria in nonalcoholic fatty liver disease--from origin to propagation. Clin Biochem 45:610-8
Di Ciaula, Agostino; Wang, David Q-H; Portincasa, Piero (2012) Gallbladder and gastric motility in obese newborns, pre-adolescents and adults. J Gastroenterol Hepatol 27:1298-305
Grattagliano, Ignazio; Russmann, Stefan; Diogo, Cátia et al. (2011) Mitochondria in chronic liver disease. Curr Drug Targets 12:879-93
Yang, Li; Li, Xiaoming; Ji, Yong et al. (2010) Effect of ezetimibe on incretin secretion in response to the intestinal absorption of a mixed meal. Am J Physiol Gastrointest Liver Physiol 299:G1003-11
Shen, Ling; Wang, David Q-H; Lo, Chun-Min et al. (2010) Estradiol increases the anorectic effect of central apolipoprotein A-IV. Endocrinology 151:3163-8
Di Ciaula, Agostino; Wang, David Q H; Wang, Helen H et al. (2010) Targets for current pharmacologic therapy in cholesterol gallstone disease. Gastroenterol Clin North Am 39:245-64, viii-ix
Wang, Helen H; Portincasa, Piero; Afdhal, Nezam H et al. (2010) Lith genes and genetic analysis of cholesterol gallstone formation. Gastroenterol Clin North Am 39:185-207, vii-viii
Wang, Helen H; Portincasa, Piero; Liu, Min et al. (2010) Effect of gallbladder hypomotility on cholesterol crystallization and growth in CCK-deficient mice. Biochim Biophys Acta 1801:138-46

Showing the most recent 10 out of 18 publications