α7-Nicotinic
acetylcholine receptor (α7nAChR) agonists confer protection against a wide variety of cytotoxic insults and suppress oxidative stress and apoptosis in various cell systems, including hepatocytes. We recently demonstrated that
nicotine, when combined with a high-fat diet (HFD), triggers oxidative stress, activates hepatocyte apoptosis, and exacerbates HFD-induced hepatic steatosis in male mice. This study evaluates whether
PNU-282987 (PNU), a specific α7nAChR agonist, is effective in preventing
nicotine plus HFD-induced hepatic steatosis. Adult C57BL6 male mice were fed a normal chow diet or HFD with 60% of calories derived from fat and received twice-daily
intraperitoneal injections of 0.75 mg/kg
body weight (BW) of
nicotine, PNU (0.26 mg/kg BW), PNU plus
nicotine, or saline for 10 weeks. PNU treatment 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 and activation of
adenosine 5'-monophosphate-activated
protein kinase (AMPK) together with inhibition of its downstream target
sterol regulatory element binding protein 1c (SREBP1c),
fatty acid synthase (FAS), and
acetyl-coenzyme A-carboxylase (ACC). We conclude that the α7nAChR agonist PNU protects against
nicotine plus HFD-induced hepatic steatosis in obese mice. PNU appears to work at various steps of signaling pathways involving suppression of oxidative stress, activation of AMPK, and inhibition of SREBP1c, FAS, and ACC. α7nAChR agonists may be an effective therapeutic strategy for ameliorating
fatty liver disease, especially in obese smokers.