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A novel GPER antagonist protects against the formation of estrogen-induced cholesterol gallstones in female mice
- Source :
- Journal of Lipid Research, Vol 61, Iss 5, Pp 767-777 (2020), J Lipid Res
- Publication Year :
- 2020
- Publisher :
- Elsevier, 2020.
-
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.­
- Subjects :
- 0301 basic medicine
medicine.medical_specialty
crystallization
medicine.drug_class
G protein-coupled estrogen receptor
Estrogen receptor
HL-60 Cells
bile
Gallstones
QD415-436
030204 cardiovascular system & hematology
Biochemistry
Receptors, G-Protein-Coupled
Mice
03 medical and health sciences
0302 clinical medicine
Endocrinology
mucin
Internal medicine
Cyclic AMP
medicine
Animals
Humans
bile salts
Research Articles
Chemistry
Antagonist
Estrogens
Cell Biology
medicine.disease
Lith
Cholesterol
030104 developmental biology
Receptors, Estrogen
Estrogen
Ovariectomized rat
Calcium
Female
Animal studies
Signal transduction
GPER
Signal Transduction
Subjects
Details
- Language :
- English
- ISSN :
- 00222275
- Volume :
- 61
- Issue :
- 5
- Database :
- OpenAIRE
- Journal :
- Journal of Lipid Research
- Accession number :
- edsair.doi.dedup.....f397e6609f56340e2a97b29a2fb3a8fd