TY - JOUR
T1 - 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
AU - Zabala, Valerie
AU - Tong, Ming
AU - Yu, Rosa
AU - Ramirez, Teresa
AU - Yalcin, Emine B.
AU - Balbo, Silvia
AU - Silbermann, Elizabeth
AU - Deochand, Chetram
AU - Nunez, Kavin
AU - Hecht, Stephen
AU - de la Monte, Suzanne M.
N1 - Funding Information:
Funding — This was supported by AA-11431, AA-12908, and a Diversity Supplement to AA-11431 from the National Institute of Alcohol Abuse and Alcoholism, T32 DK-60415 from NIDDK, and CA-81301 from the National Cancer Institute.
Publisher Copyright:
© The Author 2015. Medical Council on Alcohol and Oxford University Press. All rights reserved.
PY - 2015/3/1
Y1 - 2015/3/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84936061716&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84936061716&partnerID=8YFLogxK
U2 - 10.1093/alcalc/agu083
DO - 10.1093/alcalc/agu083
M3 - Article
C2 - 25618784
AN - SCOPUS:84936061716
SN - 0735-0414
VL - 50
SP - 118
EP - 131
JO - Alcohol and Alcoholism
JF - Alcohol and Alcoholism
IS - 2
ER -