A novel GPER antagonist protects against the formation of estrogen-induced cholesterol gallstones in female mice

Chelsea DeLeon, Helen H. Wang, Joseph Gunn, McKenna Wilhelm, Aidan Cole, Stacy Arnett, David Q.H. Wang, Christopher K. Arnatt

Research output: Contribution to journalArticle

Abstract

Many clinical studies and epidemiological investigations have clearly demonstrated that women are twice as likely to develop cholesterol gallstones as men, and oral contraceptives and other estrogen therapies dramatically increase that risk. Further, animal studies have revealed that estrogen promotes cholesterol gallstone formation through the estrogen receptor (ER) α, but not ERβ, pathway. More importantly, some genetic and pathophysiological studies have found that G protein-coupled estrogen receptor (GPER) 1 is a new gallstone gene, Lith18, on chromosome 5 in mice and produces additional lithogenic actions, working independently of ERα, to markedly increase cholelithogenesis in female mice. Based on computational modeling of GPER, a novel series of GPER-selective antagonists were designed, synthesized, and subsequently assessed for their therapeutic effects via calcium mobilization, cAMP, and ERα and ERβ fluorescence polarization binding assays. From this series of compounds, one new compound, 2-cyclohexyl-4-isopropyl-N-(4-methoxybenzyl)aniline (CIMBA), exhibits superior antagonism and selectivity exclusively for GPER. Furthermore, CIMBA reduces the formation of 17β-estradiol-induced gallstones in a dose-dependent manner in ovariectomized mice fed a lithogenic diet for 8 weeks. At 32 μg/day/kg CIMBA, no gallstones are found, even in ovariectomized ERα (-/-) mice treated with 6 μg/day 17β-estradiol and fed the lithogenic diet for 8 weeks. In conclusion, CIMBA treatment protects against the formation of estrogen-induced cholesterol gallstones by inhibiting the GPER signaling pathway in female mice. CIMBA may thus be a new agent for effectively treating cholesterol gallstone disease in women.

Original languageEnglish (US)
Pages (from-to)767-777
Number of pages11
JournalJournal of Lipid Research
Volume61
Issue number5
DOIs
StatePublished - May 1 2020

Keywords

  • Bile
  • Bile salts
  • Crystallization
  • G protein-coupled estrogen receptor
  • Lith
  • Mucin

ASJC Scopus subject areas

  • Biochemistry
  • Endocrinology
  • Cell Biology

Fingerprint Dive into the research topics of 'A novel GPER antagonist protects against the formation of estrogen-induced cholesterol gallstones in female mice'. Together they form a unique fingerprint.

  • Cite this