Estrogen receptor α, but not β, plays a major role in 17β-estradiol-induced murine cholesterol gallstones

Helen H. Wang, Nezam H. Afdhal, David Q.H. Wang

Research output: Contribution to journalArticlepeer-review

50 Scopus citations


Background & Aims: Cholesterol gallstones are more common in women than men, and exposure to oral contraceptive steroids and conjugated estrogens increases the risk for gallstones. It is hypothesized that estrogen enhances cholesterol cholelithogenesis by augmenting functions of hepatic estrogen receptors (ERs). Methods: To investigate molecular mechanisms of how estrogen influences cholesterol gallstones, we studied gonadectomized AKR/J mice of both genders that were implanted subcutaneously with pellets releasing 17β-estradiol at 0, 3, or 6 μg/day and that were fed a lithogenic diet for 12 weeks. To test the hypothesis that ERs play a pivotal role in mediating lithogenic actions of estrogen and to dissect the potential pathophysiologic roles of each receptor subtype, ERα and ERβ, in the formation of gallstones, we investigated gonadectomized mice treated with synthetic ER subtype-selective agonists or antagonists. Results: 17β-estradiol promoted gallstone formation by up-regulating hepatic expression of ERα but not ERβ, and the lithogenic actions of estrogen can be blocked completely by the antiestrogenic ICI 182,780. The ERα-selective agonist propylpyrazole, but not the ERβ-selective agonist diarylpropionitrile, augmented hepatic cholesterol output that resulted in cholesterol supersaturated bile and gallstones. Similar to the 17β-estradiol treatment, tamoxifen significantly increased biliary cholesterol secretion and gallstone prevalence in both gonadectomized females and males. Conclusions: The hepatic ERα, but not ERβ, plays a critical role in 17β-estradiol-induced cholesterol gallstones. Our findings may offer a new approach to treat gallstones by inhibiting hepatic ER activity with a liver-specific, ERα-selective antagonist.

Original languageEnglish (US)
Pages (from-to)239-249
Number of pages11
Issue number1
StatePublished - Jul 2004
Externally publishedYes


  • 17β-estradiol
  • ABC
  • CSI
  • DPN
  • ER
  • ER subtype α
  • ER subtype β
  • ERα
  • ERβ
  • ORX
  • OVX
  • adenosine triphosphate-binding cassette (transporter)
  • cholesterol saturation index
  • diarylpropionitrile
  • estrogen receptor
  • orchidectomized

ASJC Scopus subject areas

  • Hepatology
  • Gastroenterology


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