Nicotinic acetylcholine receptor α7 subunit improves energy homeostasis and inhibits inflammation in nonalcoholic fatty liver disease

Objective. Nonalcoholic fatty liver disease (NAFLD) is one of the most common liver diseases worldwide; yet, the pathogenesis of the disorder is not completely understood. The nicotinic acetylcholine receptor alpha 7 subunit (alpha 7nAChR) plays an indispensable role in the vagus nerve-regulated cholinergic anti-inflammatory pathway. Methods. In the present study, we investigated the key role of alpha 7nAChR in NAFLD development. Male wild-type (WT) and alpha 7nAChR knockout (alpha 7nAChR(-/-)) mice were fed a normal chow or a high-fat diet (HFD) for 16 weeks to induce NAFLD. Results. We found that both the mRNA and protein levels of alpha 7nAChR in the liver tissue of NAFLD mice were significantly higher than those in mice fed normal chow. There were no differences in food intake, body weight, hepatic cholesterol and triglyceride contents, and insulin sensitivity between WT and alpha 7nAChR(-/-) mice under normal condition. When the WT and alpha 7nAChR(-/-) mice were challenged with HFD, the body weight of alpha 7nAChR(-/-) mice became higher than that of WT mice. The oxygen consumption and energy expenditure in HFD-fed alpha 7nAChR(-/-) mice were significantly lower than that in HFD-fed WT mice. The HFD-fed alpha 7nAChR(-/-) mice also showed more aggravated hepatic lipid accumulation, steatosis and oxidative stress than HFD-fed WT mice. Macrophage infiltration; mRNA levels of tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), and IL-1 beta; and liver fibrosis were significantly accelerated in HFD-fed alpha 7nAChR(-/-) mice compared to that in HFD-fed WT mice. In addition, the bolus insulin injection-activated insulin signaling pathway, which was reflected by the phosphorylation of insulin receptor at Tyr1162/Tyr1163 site (p-IRTYr1162/TYr1163), insulin receptor substrate-1 at Tyr612 site (p-IRS-1(Tyr612)) and Akt at Ser473 (p-Akt(ser473)), was significantly compromised in liver tissues of HFD-fed alpha 7nAChR(-/-) mice relative to HFD-fed WT mice. Finally, pharmacologically activation of alpha 7nAChR in HFD-fed mice, with a selective agonist PNU-282987, remarkably ameliorated the hepatic steatosis, inflammatory cell infiltration and fibrosis. Conclusion. In conclusion, our results demonstrate that activation of alpha 7nAChR improves energy homeostasis and inhibits inflammation in nonalcoholic fatty liver disease. (C) 2017 Elsevier Inc. All rights reserved.