The deletion of the estrogen receptor ? 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 ? (ER?), but not ER?. To study the lithogenic mechanisms of estrogen through ER?, we investigated whether the deletion of Er? protects against gallstone formation in ovariectomized (OVX) female mice fed a lithogenic diet and treated with 17?-estradiol (E2) at 0 or 6?g/day for 56days. Our results showed that the prevalence of gallstones was reduced from 100% in OVX ER? (+/+) mice to 30% in OVX ER? (-/-) mice in response to high doses of E2 and the lithogenic diet for 56days. Hepatic cholesterol secretion was significantly diminished in OVX ER? (-/-) mice compared to OVX ER? (+/+) 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 ER? was expressed mainly in the gallbladder smooth muscle cells. High levels of E2 impaired gallbladder emptying function mostly through the ER? and cholecystokinin-1 receptor pathway, leading to gallbladder stasis in OVX ER? (+/+) mice. By contrast, gallbladder emptying function was greatly improved in OVX ER? (-/-) mice. This markedly retarded cholesterol crystallization and the growth and agglomeration of solid cholesterol crystals into microlithiasis and stones. In conclusion, the deletion of Er? 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.

SUBMITTER: de Bari O 

PROVIDER: S-EPMC4701041 | biostudies-literature | 2015 Oct

REPOSITORIES: biostudies-literature