title: A tea catechin, epigallocatechin-3-gallate, is a unique modulator of the farnesoid X receptor.
abstract: 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.
authors.affiliation: Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160, USA.
authors.forename: Guodong
authors.initials: G
authors.lastname: Li
authors.forename: Wenwei
authors.initials: W
authors.lastname: Lin
authors.forename: Juan J
authors.initials: JJ
authors.lastname: Araya
authors.forename: Taosheng
authors.initials: T
authors.lastname: Chen
authors.forename: Barbara N
authors.initials: BN
authors.lastname: Timmermann
authors.forename: Grace L
authors.initials: GL
authors.lastname: Guo
mesh_terms: D000818:Animals; D002392:Catechin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D002478:Cells, Cultured; D002635:Chenodeoxycholic Acid / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation / Q000187:drug effects*; D056945:Hep G2 Cells; D006801:Humans; D020128:Inhibitory Concentration 50; D007555:Isoxazoles / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D051958:Nuclear Receptor Coactivator 2 / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000187:drug effects* / Q000235:genetics; D013662:Tea / Q000737:chemistry*; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D002392:Catechin; D002635:Chenodeoxycholic Acid; D007555:Isoxazoles; D051958:Nuclear Receptor Coactivator 2; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D013662:Tea; D000099150:Receptor, Farnesoid X-Activated; C045651:epigallocatechin gallate; C412815:GW 4064