Farnesoid X receptor regulates SULT1E1 expression through inhibition of PGC1α binding to HNF4α

Sulfotransferase 1E1 (SULTIEI, also known as estrogen sulfotransferase) plays an important role in metabolism and detoxification of many endogenous and exogenous compounds (e.g., estrogens and flavonoids). Here we aimed to assess the effects of farnesoid X receptor (FXR) activation on SULTIEI expression, and to determine the mechanism thereof. Treatment with specific FXR agonists (i.e., GW4064 and CDCA) significantly decreased both mRNA and protein levels of SULTIEI in HepG2 cells. This was accompanied by a decrease in the enzymatic activity. The inhibitory effect was potentiated by FXR overexpression but attenuated by FXR knockdown, confirming FXR-dependent regulation of SULTIEI. Surprisingly, direct regulation of SULTIEI by FXR was unlikely because FXR did not bind to SULTIEI promoter or enhancer as revealed by chromatin immunoprecipitation (ChIP). Interestingly, SULTIEI regulation was abolished when HNF4 alpha (hepatocyte nuclear factor 4 alpha, a known activator of SULTIEI) was silenced, supporting a critical role for HNF4 alpha, in FXR regulation of SULTIEI. Furthermore, a combination of ChIP, luciferase reporter and co-immunoprecipitation assays showed that FXR inhibited HNF4 alpha, transactivation of SULTIEI by suppressed binding of the co-activator PGC1 alpha (peroxisome proliferator-activated receptor-gamma coactivator 1 alpha) to HNF4 alpha. In conclusion, FXR transcriptionally regulates SULT1E1 through inhibition of PGC1 alpha binding to HNF4 alpha. Targeting the FXR-SULT1E1 axis may represent a promising approach for management of estrogen-related diseases. (C) 2017 Elsevier Inc. All rights reserved.