1 research outputs found
Transcriptional Regulation of Human UDP-Glucuronosyltransferase 2B10 by Farnesoid X Receptor in Human Hepatoma HepG2 Cells
Little
is known about transcriptional regulators of UDP-glucuronosyltransferase
2B10 (UGT2B10), an enzyme known to glucuronidate many chemicals and
drugs such as nicotine and tricyclic antidepressants. Here, we uncovered
that UGT2B10 was transcriptionally regulated by farnesoid X receptor
(FXR), the bile acid sensing nuclear receptor. GW4064 and chenodeoxycholic
acid (two specific FXR agonists) treatment of HepG2 cells led to a
significant increase in the mRNA level of UGT2B10. The treated cells
also showed enhanced glucuronidation activities toward amitriptyline
(an UGT2B10 probe substrate). In reporter gene assays, the extent
of UGT2B10 activation by the FXR agonists was positively correlated
with the amount of cotransfected FXR. Consistently, knockdown of FXR
by shRNA attenuated the induction effect on UGT2B10 expression. Furthermore,
a combination of electrophoretic mobility shift assay and chromatin
immunoprecipitation showed that the FXR receptor trans-activated UGT2B10
through its specific binding to the −209- to −197-bp
region (an IR1 element) of the UGT2B10 promoter. In summary, our results
for the first time established FXR as a transcriptional regulator
of human UGT2B10