Ezetimibe prevents the formation of oestrogen-induced cholesterol gallstones in mice

Ornella de Bari, Helen H. Wang, Piero Portincasa, Chang Nyol Paik, Min Liu, David Q.H. Wang

Research output: Contribution to journalArticle

7 Citations (Scopus)

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. Design: 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.

Original languageEnglish (US)
Pages (from-to)1159-1168
Number of pages10
JournalEuropean Journal of Clinical Investigation
Volume44
Issue number12
DOIs
StatePublished - Jan 1 2014
Externally publishedYes

Fingerprint

Gallstones
Estrogens
Cholesterol
Intestinal Absorption
Nutrition
Bile
Estrogen Receptors
Anticholesteremic Agents
Inbred AKR Mouse
Diet
Lipids
Cholelithiasis
Liver
Hormone Replacement Therapy
Micelles
Ovariectomy
Oral Contraceptives
G-Protein-Coupled Receptors
Crystallization
Ezetimibe

Keywords

  • Bile salts
  • Biliary secretion
  • Cholesterol absorption
  • Lith gene
  • Lithogenic bile
  • Nutrition

ASJC Scopus subject areas

  • Biochemistry
  • Clinical Biochemistry

Cite this

Ezetimibe prevents the formation of oestrogen-induced cholesterol gallstones in mice. / de Bari, Ornella; Wang, Helen H.; Portincasa, Piero; Paik, Chang Nyol; Liu, Min; Wang, David Q.H.

In: European Journal of Clinical Investigation, Vol. 44, No. 12, 01.01.2014, p. 1159-1168.

Research output: Contribution to journalArticle

de Bari, Ornella ; Wang, Helen H. ; Portincasa, Piero ; Paik, Chang Nyol ; Liu, Min ; Wang, David Q.H. / Ezetimibe prevents the formation of oestrogen-induced cholesterol gallstones in mice. In: European Journal of Clinical Investigation. 2014 ; Vol. 44, No. 12. pp. 1159-1168.
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AU - Portincasa, Piero

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AU - Liu, Min

AU - Wang, David Q.H.

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AB - 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. Design: 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.

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KW - Nutrition

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