RT Journal Article
T1 AP-1 Inhibition by SR 11302 Protects Human Hepatoma HepG2 Cells from Bile Acid-Induced Cytotoxicity by Restoring the NOS-3 Expression.
A1 Gonzalez-Rubio, Sandra
A1 Linares, Clara I
A1 Aguilar-Melero, Patricia
A1 Rodriguez-Peralvarez, Manuel
A1 Montero-Alvarez, Jose L
A1 de la Mata, Manuel
A1 Ferrin, Gustavo
K1 Apoptosis
K1 Carcinoma, Hepatocellular
K1 Cyclin D1
K1 Down-Regulation
K1 Genes, Reporter
AB The harmful effects of bile acid accumulation occurring during cholestatic liver diseases have been associated with oxidative stress increase and endothelial nitric oxide synthase (NOS-3) expression decrease in liver cells. We have previously reported that glycochenodeoxycholic acid (GCDCA) down-regulates gene expression by increasing SP1 binding to the NOS-3 promoter in an oxidative stress dependent manner. In the present study, we aimed to investigate the role of transcription factor (TF) AP-1 on the NOS-3 deregulation during GCDCA-induced cholestasis. The cytotoxic response to GCDCA was characterized by 1) the increased expression and activation of TFs cJun and c-Fos; 2) a higher binding capability of these at position -666 of the NOS-3 promoter; 3) a decrease of the transcriptional activity of the promoter and the expression and activity of NOS-3; and 4) the expression increase of cyclin D1. Specific inhibition of AP-1 by the retinoid SR 11302 counteracted the cytotoxic effects induced by GCDCA while promoting NOS-3 expression recovery and cyclin D1 reduction. NOS activity inhibition by L-NAME inhibited the protective effect of SR 11302. Inducible NOS isoform was no detected in this experimental model of cholestasis. Our data provide direct evidence for the involvement of AP-1 in the NOS-3 expression regulation during cholestasis and define a critical role for NOS-3 in regulating the expression of cyclin D1 during the cell damage induced by bile acids. AP-1 appears as a potential therapeutic target in cholestatic liver diseases given its role as a transcriptional repressor of NOS-3.
PB Public Library of Science
YR 2016
FD 2016-07-20
LK http://hdl.handle.net/10668/10334
UL http://hdl.handle.net/10668/10334
LA en
NO González-Rubio S, Linares CI, Aguilar-Melero P, Rodríguez-Perálvarez M, Montero-Álvarez JL, de la Mata M, et al. AP-1 Inhibition by SR 11302 Protects Human Hepatoma HepG2 Cells from Bile Acid-Induced Cytotoxicity by Restoring the NOS-3 Expression. PLoS One. 2016 Aug 4;11(8):e0160525
DS RISalud
RD Apr 7, 2025