TY - JOUR
T1 - A tea catechin, epigallocatechin-3-gallate, is a unique modulator of the farnesoid X receptor
AU - Li, Guodong
AU - Lin, Wenwei
AU - Araya, Juan J.
AU - Chen, Taosheng
AU - Timmermann, Barbara N.
AU - Guo, Grace L.
N1 - Funding Information:
This study was supported by the National Institutes of Health funding [Grants DK081343 (GLG), GM086415 (TC) and P20-RR021940 (GLG)]; and KUMC Endowment fund (GLG). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
PY - 2012/1/15
Y1 - 2012/1/15
N2 - Farnesoid X receptor (FXR) is a ligand-activated nuclear receptor and serves as a key regulator to maintain health of the liver and intestine. Bile acids are endogenous ligands of FXR, and there are increasing efforts to identify FXR modulators to serve as biological probes and/or pharmaceutical agents. Natural FXR ligands isolated from plants may serve as models to synthesize novel FXR modulators. In this study, we demonstrated that epigallocatechin-3-gallate (EGCG), a major tea catechin, specifically and dose-dependently activates FXR. In addition, EGCG induced FXR target gene expression in vitro. Surprisingly, in a co-activator (SRC2) recruitment assay, we found that EGCG does not recruit SRC2 to FXR, but it dose-dependently inhibits recruitment of SRC2 to FXR (IC 50, 1μM) by GW6064, which is a potent FXR synthetic ligand. In addition, EGCG suppressed FXR target gene expression induced by either GW4064 or chenodeoxycholic acid in vitro. Furthermore, wild-type and FXR knockout mice treated with an acute dose of EGCG had induced mRNA expression in a subset of FXR target genes in the intestine but not in the liver. In conclusion, EGCG is a unique modulator of FXR in the intestine and may serve as an important model for future development of FXR modulators.
AB - Farnesoid X receptor (FXR) is a ligand-activated nuclear receptor and serves as a key regulator to maintain health of the liver and intestine. Bile acids are endogenous ligands of FXR, and there are increasing efforts to identify FXR modulators to serve as biological probes and/or pharmaceutical agents. Natural FXR ligands isolated from plants may serve as models to synthesize novel FXR modulators. In this study, we demonstrated that epigallocatechin-3-gallate (EGCG), a major tea catechin, specifically and dose-dependently activates FXR. In addition, EGCG induced FXR target gene expression in vitro. Surprisingly, in a co-activator (SRC2) recruitment assay, we found that EGCG does not recruit SRC2 to FXR, but it dose-dependently inhibits recruitment of SRC2 to FXR (IC 50, 1μM) by GW6064, which is a potent FXR synthetic ligand. In addition, EGCG suppressed FXR target gene expression induced by either GW4064 or chenodeoxycholic acid in vitro. Furthermore, wild-type and FXR knockout mice treated with an acute dose of EGCG had induced mRNA expression in a subset of FXR target genes in the intestine but not in the liver. In conclusion, EGCG is a unique modulator of FXR in the intestine and may serve as an important model for future development of FXR modulators.
KW - Epigallocatechin-3-gallate
KW - Farnesoid X receptor
KW - Mice
KW - Modulator
KW - Nuclear receptor
KW - Tea catechin
UR - http://www.scopus.com/inward/record.url?scp=84855789153&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84855789153&partnerID=8YFLogxK
U2 - 10.1016/j.taap.2011.11.006
DO - 10.1016/j.taap.2011.11.006
M3 - Article
C2 - 22178739
AN - SCOPUS:84855789153
SN - 0041-008X
VL - 258
SP - 268
EP - 274
JO - Toxicology and Applied Pharmacology
JF - Toxicology and Applied Pharmacology
IS - 2
ER -