AP-1 Inhibition by SR 11302 Protects Human Hepatoma HepG2 Cells from Bile Acid-Induced Cytotoxicity by Restoring the NOS-3 Expression

Autor: Patricia Aguilar-Melero, Manuel de la Mata, Clara I. Linares, Gustavo Ferrín, José Luis Montero-Álvarez, Manuel Rodríguez-Perálvarez, Sandra González-Rubio
Jazyk: angličtina
Rok vydání: 2016
Předmět:
0301 basic medicine
Physiology
Proto-Oncogene Proteins c-jun
Cytotoxicity
lcsh:Medicine
Apoptosis
Toxicology
Pathology and Laboratory Medicine
Biochemistry
chemistry.chemical_compound
Genes
Reporter
Gene expression
Medicine and Health Sciences
Bile
Cyclin D1
Cell Cycle and Cell Division
Promoter Regions
Genetic
lcsh:Science
Multidisciplinary
Cell Death
Bile acid
Liver Neoplasms
Neurochemistry
Hep G2 Cells
Body Fluids
Precipitation Techniques
Up-Regulation
NG-Nitroarginine Methyl Ester
Cell Processes
Anatomy
Neurochemicals
Proto-Oncogene Proteins c-fos
Research Article
Carcinoma
Hepatocellular
Nitric Oxide Synthase Type III
medicine.drug_class
Down-Regulation
Biology
Research and Analysis Methods
Nitric Oxide
Nitric oxide
Retinoids
03 medical and health sciences
Glycochenodeoxycholic Acid
Cholestasis
Cyclins
medicine
Glycochenodeoxycholic acid
Immunoprecipitation
Humans
Transcription factor
Cell damage
lcsh:R
Biology and Life Sciences
Cell Biology
medicine.disease
Molecular biology
Transcription Factor AP-1
Oxidative Stress
030104 developmental biology
chemistry
lcsh:Q
Neuroscience
Zdroj: PLoS ONE, Vol 11, Iss 8, p e0160525 (2016)
PLoS ONE
ISSN: 1932-6203
Popis: 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.
Databáze: OpenAIRE
Externí odkaz: