TY - JOUR
T1 - A novel GPER antagonist protects against the formation of estrogen-induced cholesterol gallstones in female mice
AU - DeLeon, Chelsea
AU - Wang, Helen H.
AU - Gunn, Joseph
AU - Wilhelm, McKenna
AU - Cole, Aidan
AU - Arnett, Stacy
AU - Wang, David Q.H.
AU - Arnatt, Christopher K.
N1 - Funding Information:
This work was supported by start-up funds from Saint Louis University (to C.K.A.) and National Institutes of Health Grants DK101793, DK106249, DK114516, AA025737 (to D.Q-H.W.), and P30 DK041296 (to the Marion Bessin Liver Research Center). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The authors declare that they have no conflicts of interest with the contents of this article. Manuscript received 20 December 2019 and in revised form 21 February 2020. Published, JLR Papers in Press, March 3, 2020 DOI https://doi.org/10.1194/jlr.RA119000592
Publisher Copyright:
Copyright © 2020 DeLeon et al. Published under exclusive license by The American Society for Biochemistry and Molecular Biology, Inc.
PY - 2020/5/1
Y1 - 2020/5/1
N2 - 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.
AB - 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.
KW - Bile
KW - Bile salts
KW - Crystallization
KW - G protein-coupled estrogen receptor
KW - Lith
KW - Mucin
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U2 - 10.1194/jlr.RA119000592
DO - 10.1194/jlr.RA119000592
M3 - Article
C2 - 32127396
AN - SCOPUS:85084961236
VL - 61
SP - 767
EP - 777
JO - Journal of Lipid Research
JF - Journal of Lipid Research
SN - 0022-2275
IS - 5
ER -