title: Ezetimibe prevents the formation of oestrogen-induced cholesterol gallstones in mice.
abstract: BACKGROUND
  Oestrogen is an important risk factor for cholesterol cholelithiasis not only in women of childbearing age taking oral contraceptives and postmenopausal women undergoing hormone replacement therapy, but also in male patients receiving oestrogen therapy for prostatic cancer. In women, hormonal changes occurring during pregnancy markedly increase the risk of developing gallstones. We investigated whether the potent cholesterol absorption inhibitor ezetimibe could prevent the formation of oestrogen-induced cholesterol gallstones in mice.
  
  
  METHODS
  Following ovariectomy, female AKR mice were implanted subcutaneously with pellets releasing 17β-estradiol at 6 μg/day and fed a lithogenic diet supplemented with ezetimibe in doses of 0 or 8 mg/kg/day for 8 weeks. Cholesterol crystallization and gallstone prevalence, lipid concentrations and composition in bile, and biliary lipid output were analysed by physical-chemical methods. Intestinal cholesterol absorption efficiency was determined by faecal dual-isotope ratio methods.
  
  
  RESULTS
  Ezetimibe inhibited intestinal cholesterol absorption, while significantly reducing hepatic secretion of biliary cholesterol. Consequently, bile was desaturated through the formation of numerous unsaturated micelles and gallstones were prevented by ezetimibe in mice exposed to high doses of oestrogen and fed the lithogenic diet. Ezetimibe did not influence mRNA levels of the classical oestrogen receptors α (ERα) and ERβ, as well as a novel oestrogen receptor the G protein-coupled receptor 30 (GPR30) in the liver.
  
  
  CONCLUSIONS
  Ezetimibe protects against the oestrogen-mediated lithogenic actions on gallstone formation in mice. Our finding may provide an efficacious novel strategy for the prevention of cholesterol gallstones in high-risk subjects, especially those exposed to high levels of oestrogen.
authors.affiliation: Department of Internal Medicine, Division of Gastroenterology and Hepatology, Saint Louis University School of Medicine, St. Louis, MO, USA.
authors.forename: Ornella
authors.initials: O
authors.lastname: de Bari
authors.forename: Helen H
authors.initials: HH
authors.lastname: Wang
authors.forename: Piero
authors.initials: P
authors.lastname: Portincasa
authors.forename: Chang-Nyol
authors.initials: CN
authors.lastname: Paik
authors.forename: Min
authors.initials: M
authors.lastname: Liu
authors.forename: David Q-H
authors.initials: DQ
authors.lastname: Wang
mesh_terms: D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology*; D001384:Azetidines / Q000494:pharmacology*; D001647:Bile Acids and Salts / Q000737:chemistry; D001659:Biliary Tract / Q000378:metabolism; D002784:Cholesterol / Q000378:metabolism; D004958:Estradiol / Q000633:toxicity; D004967:Estrogens / Q000633:toxicity; D000069438:Ezetimibe; D005260:Female; D042882:Gallstones / Q000517:prevention & control*; D007408:Intestinal Absorption / Q000187:drug effects; D050356:Lipid Metabolism / Q000502:physiology; D008297:Male; D008806:Mice, Inbred AKR; D012333:RNA, Messenger / Q000378:metabolism
chemical_list: D000924:Anticholesteremic Agents; D001384:Azetidines; D001647:Bile Acids and Salts; D004967:Estrogens; D012333:RNA, Messenger; D004958:Estradiol; D002784:Cholesterol; D000069438:Ezetimibe
keywords: Bile salts; Lith gene; biliary secretion; cholesterol absorption; lithogenic bile; nutrition