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

Abstract

BaCKgRoUND aND aIMS: 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. appRoaCH aND ReSUltS: 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. CoNClUSIoNS: 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. (Hepatology 2020;72:2077-2089). E pidemiological investigations and clinical studies have clearly demonstrated that estrogen is a critical risk factor for cholesterol cholelithiasis because gallstones are more common in women than in men at all ages in every population studied. (1) The biological effects of estrogen are ascribed to transcriptional modulation of target genes through two classical estrogen receptors (ERs), subtypes α and β (ERα and ERβ). Using quantitative real-time PCR techniques, hepatic expression of the Erα gene is found to be ∼50-fold higher compared with that of Erβ, suggesting that ERα is a major steroid hormone receptor for exerting the biological effects of estrogen in the liver. (2) To study the molecular mechanisms of how estrogen influences gallstone formation, we

G Protein-Coupled Estrogen Receptor, GPER1, Offers a Novel Target for the Treatment of Digestive Diseases

“…As found by a powerful genetic quantitative trait locus (QTL) analysis, Gper1 is a new gallstone gene, Lith18, on chromosome 5 in mice (62)(63)(64)(65)(66). GPER1 activated by its agonist, G-1, enhances cholelithogenesis by deterring expression of cholesterol 7a-hydroxylase, the rate-limiting enzyme for the classical pathway of bile salt synthesis (67). These metabolic abnormalities greatly increase biliary cholesterol concentrations in company with hepatic hyposecretion of biliary bile salts, leading to cholesterol-supersaturated gallbladder bile and accelerating cholesterol crystallization (68).…”

“…This suggests that GPER1 could impair gallbladder motility, working independently of ESR1, as both can cause sluggish gallbladder contractility from different mechanisms. Indeed, G-1 impairs gallbladder emptying through the GPER1 pathway in mice, leading to sluggish gallbladder motility and accelerating the development of biliary sludge in the early stage of gallstone formation (67).…”

Astragalus Polysaccharides Ameliorate Diet-Induced Gallstone Formation by Modulating Synthesis of Bile Acids and the Gut Microbiota

“…First, the relative BA composition in BA pools in the humans and mice is different ( de Aguiar Vallim et al, 2013 ). Mouse models of gallstones established with a combination of cholesterol and cholic acid are used widely ( Wang et al, 2018 ; Munoz et al, 2019 ; Wang et al, 2020a ), but the pathogenesis of CG formation in mice and humans is not identical. For example, humans do not ingest CA via the diet.…”

Membrane-Initiated Estrogen, Androgen, and Progesterone Receptor Signaling in Health and Disease

“…In any case, GPER is considered to mediate rapid E2 effects on neuroprotection ( 103 ). In the kidney, GPER is believed to mediate the actions of E2 on natriuresis ( 104 ) and seems to mediate E2 lithogenic actions independently of ERα to increase gallstone formation susceptibility in female mice ( 105 ). GPER is expressed in peripheral B and T lymphocytes as well as in monocytes, eosinophils, and neutrophils and is believed to mediate E2’s effects in immune cells ( 106 ).…”