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Horm Metab Res 2014; 46(08): 568-573
DOI: 10.1055/s-0034-1375610
Endocrine Research
© Georg Thieme Verlag KG Stuttgart · New York

Additive Effects of Nicotine and High-Fat Diet on Hepatocellular Apoptosis in Mice: Involvement of Caspase 2 and Inducible Nitric Oxide Synthase-Mediated Intrinsic Pathway Signaling

R. Ivey
1   Division of Endocrinology, Metabolism and Molecular Medicine, Department of Internal Medicine, Charles R. Drew University, Los Angeles, USA
,
M. Desai
1   Division of Endocrinology, Metabolism and Molecular Medicine, Department of Internal Medicine, Charles R. Drew University, Los Angeles, USA
,
K. Green
1   Division of Endocrinology, Metabolism and Molecular Medicine, Department of Internal Medicine, Charles R. Drew University, Los Angeles, USA
,
I. Sinha-Hikim
1   Division of Endocrinology, Metabolism and Molecular Medicine, Department of Internal Medicine, Charles R. Drew University, Los Angeles, USA
2   David Geffen School of Medicine at University of California, Los Angeles (UCLA), Los Angeles, USA
,
T. C. Friedman
1   Division of Endocrinology, Metabolism and Molecular Medicine, Department of Internal Medicine, Charles R. Drew University, Los Angeles, USA
2   David Geffen School of Medicine at University of California, Los Angeles (UCLA), Los Angeles, USA
,
A. P. Sinha-Hikim
1   Division of Endocrinology, Metabolism and Molecular Medicine, Department of Internal Medicine, Charles R. Drew University, Los Angeles, USA
› Author Affiliations
Further Information

Publication History

received 25 November 2013

accepted 10 April 2014

Publication Date:
15 May 2014 (online)

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Abstract

Smoking is a major risk factor for diabetes and cardiovascular disease and may contribute to nonalcoholic fatty liver disease (NAFLD). The health risk associated with smoking is exaggerated by obesity and is the leading causes of morbidity and mortality worldwide. We recently demonstrated that combined treatment with nicotine and a high-fat diet (HFD) triggers greater oxidative stress, activates hepatocellular apoptosis, and exacerbates HFD-induced hepatic steatosis. Given that hepatocellular apoptosis plays a pivotal role in the pathogenesis of NAFLD, using this model of exacerbated hepatic steatosis, we elucidated the signal transduction pathways involved in HFD plus nicotine-induced liver cell death. Adult C57BL6 male mice were fed a normal chow diet or HFD with 60% of calories derived from fat and received twice daily IP injections of 0.75 mg/kg BW of nicotine or saline for 10 weeks. High-resolution light microscopy revealed markedly higher lipid accumulation in hepatocytes from mice received HFD plus nicotine, compared to mice on HFD alone. Addition of nicotine to HFD further resulted in an increase in the incidence of hepatocellular apoptosis and was associated with activation of caspase 2, induction of inducible nitric oxide synthase (iNOS), and perturbation of the BAX/BCL-2 ratio. Together, our data indicate the involvement of caspase 2 and iNOS-mediated apoptotic signaling in nicotine plus HFD-induced hepatocellular apoptosis. Targeting the caspase 2-mediated death pathway may have a protective role in development and progression of NAFLD.

Key words

nicotine - high-fat diet - oxidative stress - caspase 2 - iNOS - apoptosis - hepatic steatosis

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