Activation of Estrogen Receptor G Protein-Coupled Receptor 30 Enhances Cholesterol Cholelithogenesis in Female Mice.

Helen H Wang, Ornella de Bari, Christopher K Arnatt, Min Liu, Piero Portincasa, David Q-H Wang

Hepatology (Baltimore, Md.) 2020 Dec

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Estrogen is an important risk factor for cholesterol gallstone disease because women are twice as likely as men to form gallstones. The classical estrogen receptor α (ERα), but not ERβ, in the liver plays a critical role in the formation of estrogen-induced gallstones in female mice. The molecular mechanisms underlying the lithogenic effect of estrogen on gallstone formation have become more complicated with the identification of G protein-coupled receptor 30 (GPR30), an estrogen receptor. We investigated the biliary and gallstone phenotypes in ovariectomized female GPR30-/- , ERα-/- , and wild-type mice injected intramuscularly with the potent GPR30-selective agonist G-1 at 0 or 1 μg/day and fed a lithogenic diet for 8 weeks. The activation of GPR30 by G-1 enhanced cholelithogenesis by suppressing expression of cholesterol 7α-hydroxylase, the rate-limiting enzyme for the classical pathway of bile salt synthesis. These metabolic abnormalities led to an increase in biliary cholesterol concentrations in company with hepatic hyposecretion of biliary bile salts, thereby inducing cholesterol-supersaturated gallbladder bile and accelerating cholesterol crystallization. G-1 also impairs gallbladder emptying, leading to sluggish gallbladder motility and promoting the development of biliary sludge in the early stage of gallstone formation. The prevalence rates of gallstones were 80% in wild-type and ERα-/- mice treated with G-1 compared to 10% in wild-type mice receiving no G-1. However, no gallstones were formed in GPR30-/- mice treated with G-1. GPR30 produces additional lithogenic actions, working independently of ERα, to increase susceptible to gallstone formation in female mice; both GPR30 and ERα are potential therapeutic targets for cholesterol gallstone disease, particularly in women and patients exposed to high levels of estrogen. © 2020 by the American Association for the Study of Liver Diseases.

Citation

Helen H Wang, Ornella de Bari, Christopher K Arnatt, Min Liu, Piero Portincasa, David Q-H Wang. Activation of Estrogen Receptor G Protein-Coupled Receptor 30 Enhances Cholesterol Cholelithogenesis in Female Mice. Hepatology (Baltimore, Md.). 2020 Dec;72(6):2077-2089