Department of Pharmacy, Shanghai Tenth People's Hospital, Tongji University, Shanghai, China; Department of Pharmacology, School of Medicine, Tongji University, Shanghai, China.
Department of Biliary Tract Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China.
Metabolism. 2018 Feb;79:52-63. doi: 10.1016/j.metabol.2017.11.002. Epub 2017 Nov 10.
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), insulin receptor substrate-1 at Tyr612 site (p-IRS-1) and Akt at Ser473 (p-Akt), 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.
目的：非酒精性脂肪性肝病（NAFLD）是全球最常见的肝脏疾病之一；然而，其发病机制尚不完全清楚。烟碱型乙酰胆碱受体α7 亚单位（α7nAChR）在迷走神经调节的胆碱能抗炎途径中起着不可或缺的作用。
方法：在本研究中，我们研究了 α7nAChR 在 NAFLD 发展中的关键作用。雄性野生型（WT）和α7nAChR 敲除（α7nAChR）小鼠分别用正常饲料或高脂肪饮食（HFD）喂养 16 周，以诱导 NAFLD。
结果：我们发现，NAFLD 小鼠肝组织中 α7nAChR 的 mRNA 和蛋白水平均明显高于正常饲料喂养的小鼠。在正常条件下，WT 和 α7nAChR 小鼠的食物摄入量、体重、肝胆固醇和甘油三酯含量以及胰岛素敏感性均无差异。当 WT 和 α7nAChR 小鼠接受 HFD 挑战时，α7nAChR 小鼠的体重高于 WT 小鼠。HFD 喂养的 α7nAChR 小鼠的耗氧量和能量消耗明显低于 HFD 喂养的 WT 小鼠。与 HFD 喂养的 WT 小鼠相比，HFD 喂养的 α7nAChR 小鼠的肝脂质积聚、脂肪变性和氧化应激更为严重。HFD 喂养的 α7nAChR 小鼠的巨噬细胞浸润、肿瘤坏死因子-α（TNF-α）、白细胞介素-6（IL-6）和白细胞介素-1β（IL-1β）的 mRNA 水平以及肝纤维化明显加速。此外，HFD 喂养的 α7nAChR 小鼠的胰岛素信号通路被激活，胰岛素受体在 Tyr1162/Tyr1163 位点（p-IR）、胰岛素受体底物-1 在 Tyr612 位点（p-IRS-1）和 Akt 在 Ser473 位点（p-Akt）的磷酸化明显受损，与 HFD 喂养的 WT 小鼠相比。最后，用选择性激动剂 PNU-282987 激活 HFD 喂养的小鼠的 α7nAChR，可显著改善肝脂肪变性、炎症细胞浸润和纤维化。
结论：总之，我们的结果表明，激活α7nAChR 可改善非酒精性脂肪性肝病中的能量平衡并抑制炎症。
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