FP05-6 Additive Effects of Nicotine and High-Fat Diet On Hepatic Steatosis and Hepatocellular Apoptosis in Mice: Involvement of Caspase 2 and Inducible Nitric Oxide Synthase-Mediated Intrinsic Pathway Signaling

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: FP05-Lipids: Regulation & Mechanism of Disease
Basic
Saturday, June 15, 2013: 11:00 AM-11:30 AM
Presentation Start Time: 11:25 AM
Room 133 (Moscone Center)

Poster Board SAT-723
Rasheed Ivey*1, Indrani Sinha-Hikim2, Merra Deasi1, Chang-Sung Shin1, Theodore C Friedman1 and Amiya P Sinha-Hikim2
1Charles R. Drew University, Los Angeles, CA, 2Charles R. Drew University of Medicine and Science, Los Angeles, CA
Background and Objective: Smoking is a major risk factor for diabetes and cardiovascular disease and may contribute to non-alcoholic 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 (Endocrinology 153: 5809-5820, 2012). 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.

Experimental Design: 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.

Results: Light and electron microscopy revealed markedly higher lipid accumulation with lower content of endoplasmic reticulum and glycogen in hepatocytes from mice on 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 (an initiator caspase working upstream of kinase activation and mitochondria-dependent apoptotic pathway), p38 mitogen-activated protein kinase (MAPK), induction of inducible nitric oxide synthase (iNOS), and perturbation of the BAX/BCL-2 ratio.

Conclusions: Together, our data indicate the involvement of caspase 2, p38 MAPK, and iNOS that though activation of intrinsic pathway signaling promotes hepatocellular apoptosis and further worsen HFD-induced hepatic steatosis in obese mice. Targeting the caspase 2-mediated death pathway may have a protective role in development and progression of NAFLD.

Nothing to Disclose: RI, IS, MD, CSS, TCF, APS

*Please take note of The Endocrine Society's News Embargo Policy at http://www.endo-society.org/endo2013/media.cfm

Sources of Research Support: This work was supported by National Institutes of Health Minority Institution Drug Abuse Research Program Grant (R24DA017298)
<< Previous Abstract | Next Abstract