Additive Effects of Nicotine and High-Fat Diet on Hepatic Steatosis and Hepatocellular Apoptosis: Role of Aplha-7-Nicotinic Acetylcholine Receptors

Presentation Number: MON 518
Date of Presentation: April 3rd, 2017

Mohammad Kamrul Hasan*1, Theodore C Friedman2, Indrani Sinha-Hikim1, Jorge Espinoza-Derout1, Carl Sims1, Desean L. Lee1 and Amiya P Sinha-Hikim1
1Charles R Drew University of Medicine and Science, Los Angeles, CA, 2David Geffen School of Medicine, UCLA

Abstract

Background and Objective: Cigarette smoking is a major risk factor for diabetes, cardiovascular disease and, nonalcoholic fatty liver disease. The health risk associated with smoking can be exaggerated by obesity. We previously, 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. Here, using PNU-282987 or PNU, a specific a7 nicotinic acetylcholine receptor (a7nAChR) agonist, and a commonly used model of diet-induced obesity, we elucidated the role of a7-nAChR in nicotine-induced weight loss and hepatic steatosis in mice on a HFD.

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: As expected, nicotine blocked the HFD-induced weight gain and exacerbated HFD-induced hepatic steatosis. PNU alone significantly (P<0.05) though modestly, reduced body weight and cumulative food intake in HFD mice. Notably, addition of PNU to nicotine-treated mice on a HFD was effective in attenuating nicotine plus HFD-induced increase in hepatic triglyceride levels, hepatocyte apoptosis and hepatic steatosis. The preventive effects of PNU on nicotine plus HFD-induced hepatic steatosis were mediated by suppression of oxidative stress, activation of silent information regulator 1 (SIRT1) and AMP-activated protein kinase (AMPK) together with inhibition of its downstream target acetyl-coenzyme A-carboxylase (ACC). Furthermore, expression of Sterol Regulatory Element Binding Protein 1c (SREBP1c) and Fatty Acid Synthase (FAS) were also reduced in PNU treated HFD fed mice.

Conclusions: We conclude that pharmacological activation of a7nAChR by PNU protects nicotine plus HFD-induced hepatic steatosis in obese mice. PNU appears to works at various steps of signaling pathway involving suppression of oxidative stress, activation SIRT-1 and AMPK, and inhibition of ACC. Targeting the a7nAChR may represent a valuable therapeutic option in mitigating the detrimental effects of nicotine plus a HFD on hepatic steatosis.

 

Nothing to Disclose: MKH, TCF, IS, JE, CS, DLL, APS