Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Androstadienes / pharmacology
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Catalase / genetics
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Catalase / metabolism
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Cell Extracts
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Cell Line
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Cytochrome P-450 Enzyme System / genetics
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Cytochrome P450 Family 2
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Cytoprotection
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Ethanol / metabolism*
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Gene Expression Regulation, Enzymologic / drug effects
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Gene Expression Regulation, Enzymologic / genetics
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Glutamate-Cysteine Ligase / genetics
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Glutamate-Cysteine Ligase / metabolism
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Glutathione / metabolism
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Hepatocyte Growth Factor / metabolism*
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Hepatocyte Growth Factor / therapeutic use
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Hepatocytes / drug effects
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Hepatocytes / metabolism*
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Hepatocytes / pathology
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Humans
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Lipid Peroxidation / drug effects
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Lipid Peroxidation / genetics
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Liver Diseases, Alcoholic / drug therapy
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NF-kappa B / antagonists & inhibitors
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Neurophysins / genetics
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Oxidative Stress
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Peptides / pharmacology
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Protein Precursors / genetics
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Proto-Oncogene Proteins c-akt / antagonists & inhibitors
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Signal Transduction / drug effects
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Signal Transduction / genetics
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Superoxide Dismutase / genetics
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Superoxide Dismutase / metabolism
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Superoxide Dismutase-1
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Transfection
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Transgenes / genetics
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Vasopressins / genetics
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Wortmannin
Substances
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AVP protein, human
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Androstadienes
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Cell Extracts
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NF-kappa B
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Neurophysins
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Peptides
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Protein Precursors
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SN50 peptide
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SOD1 protein, human
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Vasopressins
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Ethanol
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Hepatocyte Growth Factor
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Cytochrome P-450 Enzyme System
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Catalase
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CYP2F1 protein, human
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Cytochrome P450 Family 2
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Superoxide Dismutase
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Superoxide Dismutase-1
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Proto-Oncogene Proteins c-akt
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Glutamate-Cysteine Ligase
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Glutathione
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Wortmannin