title: The deletion of the estrogen receptor α gene reduces susceptibility to estrogen-induced cholesterol cholelithiasis in female mice.
abstract: Compelling evidence has demonstrated that estrogen is a critical risk factor for gallstone formation and enhances cholesterol cholelithogenesis through the hepatic estrogen receptor α (ERα), but not ERβ. To study the lithogenic mechanisms of estrogen through ERα, we investigated whether the deletion of Erα protects against gallstone formation in ovariectomized (OVX) female mice fed a lithogenic diet and treated with 17β-estradiol (E2) at 0 or 6μg/day for 56days. Our results showed that the prevalence of gallstones was reduced from 100% in OVX ERα (+/+) mice to 30% in OVX ERα (-/-) mice in response to high doses of E2 and the lithogenic diet for 56days. Hepatic cholesterol secretion was significantly diminished in OVX ERα (-/-) mice compared to OVX ERα (+/+) mice even fed the lithogenic diet and treated with E2 for 56days. These alterations decreased bile lithogenicity by reducing cholesterol saturation index of gallbladder bile. Immunohistochemical studies revealed that ERα was expressed mainly in the gallbladder smooth muscle cells. High levels of E2 impaired gallbladder emptying function mostly through the ERα and cholecystokinin-1 receptor pathway, leading to gallbladder stasis in OVX ERα (+/+) mice. By contrast, gallbladder emptying function was greatly improved in OVX ERα (-/-) mice. This markedly retarded cholesterol crystallization and the growth and agglomeration of solid cholesterol crystals into microlithiasis and stones. In conclusion, the deletion of Erα reduces susceptibility to the formation of E2-induced gallstones by diminishing hepatic cholesterol secretion, desaturating gallbladder bile, and improving gallbladder contraction function in female mice.
authors.affiliation: Department of Internal Medicine, Division of Gastroenterology and Hepatology, Saint Louis University School of Medicine, St. Louis, MO 63104, USA.
authors.forename: Ornella
authors.initials: O
authors.lastname: de Bari
authors.affiliation: Department of Internal Medicine, Division of Gastroenterology and Hepatology, Saint Louis University School of Medicine, St. Louis, MO 63104, USA.
authors.forename: Helen H
authors.initials: HH
authors.lastname: Wang
authors.affiliation: Clinica Medica "A. Murri", Department of Biomedical Sciences and Human Oncology, University of Bari Medical School, Bari, Italy.
authors.forename: Piero
authors.initials: P
authors.lastname: Portincasa
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Cincinnati College of Medicine, Cincinnati, OH 45237, USA.
authors.forename: Min
authors.initials: M
authors.lastname: Liu
authors.affiliation: Department of Internal Medicine, Division of Gastroenterology and Hepatology, Saint Louis University School of Medicine, St. Louis, MO 63104, USA. Electronic address: dwang15@slu.edu.
authors.forename: David Q-H
authors.initials: DQ
authors.lastname: Wang
keywords: Bile flow; Bile salts; Biliary secretion; Cholesterol crystallization; Gallbladder motility; Lith gene