Hepatocyte growth factor protects hepatocytes against oxidative injury induced by ethanol metabolism.
Hepatocyte growth factor (HGF) is involved in many cellular responses, such as mitogenesis and apoptosis protection; however, its effect against oxidative injury induced by ethanol metabolism is not well understood. The aim of this work was to address the mechanism of HGF-induced protection against ethanol-generated oxidative stress damage in the human cell line VL-17A (cytochrome P450 2E1/alcohol dehydrogenase-transfected HepG2 cells). Cells were pretreated with 50 ng/ml HGF for 12 h and then treated with 100 mM ethanol for 0-48 h. Some parameters of oxidative damage were evaluated. We found that ethanol induced peroxide formation (3.3-fold) and oxidative damage as judged by lipid peroxidation (5.4-fold). Damage was prevented by HGF. To address the mechanisms of HGF-induced protection we investigated the cellular antioxidant system. We found that HGF increased the GSH/GSSG ratio, as well as SOD1, catalase, and gamma-glutamylcysteine synthetase expression. To explore the signaling pathways involved in this process, VL-17A cells were pretreated with inhibitors against PI3K, Akt, and NF-kappaB. We found that all treatments decreased the expression of the antioxidant enzymes, thus abrogating the HGF-induced protection against oxidative stress. Our results demonstrate that HGF protects cells from the oxidative damage induced by ethanol metabolism by a mechanism driven by NF-kappaB and PI3K/Akt signaling.
Valdés-Arzate
Argelia
A
Departamento de Ciencias de la Salud, DCBS, Universidad Autónoma Metropolitana-Iztapalapa, 09340 México, DF, México.
Luna
Armando
A
Bucio
Leticia
L
Licona
Cynthia
C
Clemens
Dahn L
DL
Souza
Verónica
V
Hernandez
Elizabeth
E
Kershenobich
David
D
Gutiérrez-Ruiz
María Concepción
MC
Gómez-Quiroz
Luis Enrique
LE
D000730:Androstadienes / Q000494:pharmacology; D002374:Catalase / Q000235:genetics / Q000378:metabolism; D002457:Cell Extracts; D002460:Cell Line; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics; D000072467:Cytochrome P450 Family 2; D019610:Cytoprotection; D000431:Ethanol / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects / Q000235:genetics; D005721:Glutamate-Cysteine Ligase / Q000235:genetics / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D017228:Hepatocyte Growth Factor / Q000378:metabolism* / Q000627:therapeutic use; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D015227:Lipid Peroxidation / Q000187:drug effects / Q000235:genetics; D008108:Liver Diseases, Alcoholic / Q000188:drug therapy; D016328:NF-kappa B / Q000037:antagonists & inhibitors; D009481:Neurophysins / Q000235:genetics; D018384:Oxidative Stress; D010455:Peptides / Q000494:pharmacology; D011498:Protein Precursors / Q000235:genetics; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism; D000072105:Superoxide Dismutase-1; D014162:Transfection; D019076:Transgenes / Q000235:genetics; D014667:Vasopressins / Q000235:genetics; D000077191:Wortmannin
C438657:AVP protein, human; D000730:Androstadienes; D002457:Cell Extracts; D016328:NF-kappa B; D009481:Neurophysins; D010455:Peptides; D011498:Protein Precursors; C118258:SN50 peptide; C000606290:SOD1 protein, human; D014667:Vasopressins; D000431:Ethanol; D017228:Hepatocyte Growth Factor; D003577:Cytochrome P-450 Enzyme System; D002374:Catalase; C110332:CYP2F1 protein, human; D000072467:Cytochrome P450 Family 2; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D051057:Proto-Oncogene Proteins c-akt; D005721:Glutamate-Cysteine Ligase; D005978:Glutathione; D000077191:Wortmannin