Potential contributions of the tobacco nicotine-derived nitrosamine ketone (NNK) in the pathogenesis of steatohepatitis in a chronic plus binge rat model of alcoholic liver disease
| Autor: | Silvia Balbo, Emine B. Yalcin, Chetram Deochand, Rosa Yu, Teresa Ramirez, Stephen S. Hecht, Kavin M Nunez, Suzanne M. de la Monte, Ming Tong, Elizabeth Silbermann, Valerie Zabala |
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| Rok vydání: | 2015 |
| Předmět: |
medicine.medical_specialty
Alcoholic liver disease endocrine system Nitrosamines medicine.medical_treatment Mitochondria Liver medicine.disease_cause Endoplasmic Reticulum Binge Drinking Receptor IGF Type 1 Metabolic and Genetic Lipid peroxidation chemistry.chemical_compound Necrosis Insulin resistance Fibrosis Internal medicine mental disorders medicine Animals Insulin Rats Long-Evans Insulin-Like Growth Factor I Liver Diseases Alcoholic Ethanol business.industry Central Nervous System Depressants General Medicine medicine.disease Receptor Insulin Rats Alcoholism Disease Models Animal Endocrinology chemistry Liver Nitrosamine Carcinogens Hepatocytes Steatohepatitis Insulin Resistance business Oxidative stress Fatty Liver Alcoholic Signal Transduction |
| Zdroj: | Alcohol and alcoholism (Oxford, Oxfordshire). 50(2) |
| ISSN: | 1464-3502 |
| Popis: | Aims: Alcoholic liver disease (ALD) is linked to binge drinking and cigarette smoking. Heavy chronic ± binge alcohol, or low-level exposures to dietary nitrosamines cause steatohepatitis with insulin resistance and oxidative stress in animal models. This study examines hepatotoxic effects of sub-mutagenic exposures to tobacco-specific nitrosamine (NNK) in relation to ALD. Methods: Long Evans rats were fed liquid diets containing 0 or 26% (caloric) ethanol (EtOH) for 8 weeks. In Weeks 3 through 8, rats were treated with NNK (2 mg/kg) or saline by i.p. injection, 3×/week, and in Weeks 7 and 8, EtOH-fed rats were binge-administered 2 g/kg EtOH 3×/week; controls were given saline. Results: EtOH ± NNK caused steatohepatitis with necrosis, disruption of the hepatic cord architecture, ballooning degeneration, early fibrosis, mitochondrial cytopathy and ER disruption. Severity of lesions was highest in the EtOH+NNK group. EtOH and NNK inhibited insulin/IGF signaling through Akt and activated pro-inflammatory cytokines, while EtOH promoted lipid peroxidation, and NNK increased apoptosis. O6 -methyl-Guanine adducts were only detected in NNK-exposed livers. Conclusion: Both alcohol and NNK exposures contribute to ALD pathogenesis, including insulin/IGF resistance and inflammation. The differential effects of EtOH and NNK on adduct formation are critical to ALD progression among alcoholics who smoke. |
| Databáze: | OpenAIRE |
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