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

Abstract

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 α7 subunit (α7nAChR) plays an indispensable role in the vagus nerve-regulated cholinergic anti-inflammatory pathway.

Methods: In the present study, we investigated the key role of α7nAChR in NAFLD development. Male wild-type (WT) and α7nAChR knockout (α7nAChR^-/-) mice were fed a normal chow or a high-fat diet (HFD) for 16weeks to induce NAFLD.

Results: We found that both the mRNA and protein levels of α7nAChR 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 α7nAChR^-/- mice under normal condition. When the WT and α7nAChR^-/- mice were challenged with HFD, the body weight of α7nAChR^-/- mice became higher than that of WT mice. The oxygen consumption and energy expenditure in HFD-fed α7nAChR^-/- mice were significantly lower than that in HFD-fed WT mice. The HFD-fed α7nAChR^-/- 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-α (TNF-α), interleukin-6 (IL-6), and IL-1β; and liver fibrosis were significantly accelerated in HFD-fed α7nAChR^-/- 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-IR^{Tyr1162/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 α7nAChR^-/- mice relative to HFD-fed WT mice. Finally, pharmacologically activation of α7nAChR 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 α7nAChR improves energy homeostasis and inhibits inflammation in nonalcoholic fatty liver disease.

Keywords: Insulin signaling pathway; Nicotinic acetylcholine receptor α7 subunit; Nonalcoholic fatty liver disease; Steatohepatitis; Steatosis.