# GPR30 and hepatic cholesterol metabolism

> **NIH NIH R01** · ALBERT EINSTEIN COLLEGE OF MEDICINE · 2020 · $467,461

## Abstract

Abstract
Clinical and epidemiological studies have clearly demonstrated that women are twice as likely as men to form
cholesterol gallstones at all ages studied, indicating that estrogen is an important risk factor for cholesterol
gallstone disease. Oral contraceptives and conjugated estrogens significantly increase gallstone prevalence in
premenopausal and postmenopausal women. Similar lithogenic effects are also found in men with prostate
cancer during postoperative estrogen therapy. All these studies indicate that high susceptibility to gallstones in
women compared with men is related to differences in how the liver metabolizes cholesterol in response to
estrogen. Our published studies have shown that the classical estrogen receptor α (ERα), but not ERβ, in the
liver plays a critical role in estrogen-induced gallstones in female mice. The molecular mechanisms underlying
the lithogenic role of estrogen in gallstone formation have become more complicated with the identification of
the G protein-coupled receptor 30 (GPR30), a novel estrogen receptor. Our genetic analysis has found that
Gpr30 is a new gallstone gene, Lith18, in mice. Our published results have established a novel concept that
GPR30 is involved in estrogen-dependent lithogenic actions, working independently of ERα, as both GPR30
and ERα can promote the formation of estrogen-induced gallstones through different pathways. However,
identifying the lithogenic mechanisms of GPR30 has been a focal point of interest because it remains elusive
how GPR30 increases susceptibility to estrogen-induced gallstones at a molecular level. We hypothesize that
GPR30 activated by estrogen enhances cholelithogenesis through the epidermal growth factor
receptor (EGFR) signaling pathway by disrupting hepatic bile acid metabolism, promoting biliary
cholesterol hypersecretion, and impairing gallbladder emptying and refilling. This hypothesis is based on
our new preliminary data showing that GPR30 is localized predominantly in the endoplasmic reticulum of
hepatocytes, which is completely different from ERα that resides mainly in the nucleus of hepatocytes. We plan
to accomplish our goals by pursuing the following three specific aims: First, we will elucidate the mechanisms
whereby the activation of GPR30 enhances the bile lithogenicity by inhibiting hepatic bile acid synthesis
through the EGFR pathway. Second, we will investigate the mechanisms underlying the critical role of GPR30
in promoting biliary cholesterol hypersecretion. Third, we will explore whether GPR30 impairs gallbladder
motility that accounts for rapid growth and agglomeration of solid cholesterol crystals to microlithiasis. After
completing the proposed studies, our results will present a new view on how GPR30 regulates cholesterol and
bile acid metabolism in the liver, bile, and gallbladder, and will develop novel concepts to elucidate the vital
roles of GPR30 in driving the initiation of supersaturated bile and cholesterol crystallization...

## Key facts

- **NIH application ID:** 10072264
- **Project number:** 1R01DK126369-01
- **Recipient organization:** ALBERT EINSTEIN COLLEGE OF MEDICINE
- **Principal Investigator:** DAVID Q WANG
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $467,461
- **Award type:** 1
- **Project period:** 2020-07-10 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10072264

## Citation

> US National Institutes of Health, RePORTER application 10072264, GPR30 and hepatic cholesterol metabolism (1R01DK126369-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10072264. Licensed CC0.

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