Abstract：
Obesity is a major cause of nonalcohol fatty liver disease (NAFLD), which is characterized by hepatic fibrosis, lipotoxicity, inflammation, and apoptosis. Previous studies have shown that an imbalance in the autonomic nervous system is closely related to the pathogenesis of NAFLD. In this study, we investigated the effects of pyridostigmine (PYR), a cholinesterase (AChE) inhibitor, on HFD-induced liver injury and explored the potential mechanisms involving mitochondrial damage and oxidative stress. A murine model of HFD-induced obesity was established using the C57BL/6 mice, and PYR (3 mg/kg/d) or placebo was administered for 20 weeks. PYR reduced the body weight and liver weight of the HFD-fed mice. Additionally, the serum levels of IL-6, TNF-α, cholesterol, and triglyceride were significantly lower in the PYR-treated versus the untreated mice, corresponding to a decrease in hepatic fibrosis, lipid accumulation, and apoptosis in the former. Furthermore, the mitochondrial morphology improved significantly in the PYR-treated group. Consistently, PYR upregulated ATP production and the mRNA level of the mitochondrial dynamic factors OPA1, Drp1 and Fis1, and the mitochondrial unfolded protein response (UPRmt) factors LONP1 and HSP60. Moreover, PYR treatment activated the Keap1/Nrf2 pathway and upregulated HO-1 and NQO-1, which mitigated oxidative injury as indicated by decreased 8-OHDG, MDA and H2 O2 levels, and increased SOD activity. Finally, PYR elevated acetylcholine (ACh) levels by inhibiting AChE, and upregulated the α7nAChR and M3AChR proteins in the HFD-fed mice. PYR alleviated obesity-induced hepatic injury in mice by mitigating mitochondrial damage and oxidative stress via α7nAChR and M3AChR.
摘要：
肥胖是非酒精性脂肪性肝病（NAFLD）的主要原因，其特征是肝纤维化，脂毒性，炎症,和凋亡。以往的研究表明，自主神经系统的失衡与NAFLD的发病密切相关。在这项研究中,我们研究了吡啶斯的明（PYR）的作用，胆碱酯酶（AChE）抑制剂，探讨HFD引起的肝损伤，并探讨线粒体损伤和氧化应激的潜在机制。用C57BL/6小鼠建立HFD诱导的肥胖小鼠模型,和PYR（3mg/kg/d）或安慰剂给药20周。PYR降低HFD喂养小鼠的体重和肝脏重量。此外,血清IL-6、TNF-α、胆固醇,与未治疗的小鼠相比，PYR治疗的小鼠中的甘油三酯显着降低，对应于肝纤维化的减少，脂质积累，前者和凋亡。此外，PYR治疗组线粒体形态明显改善.始终如一，PYR上调ATP的产生和线粒体动态因子OPA1，Drp1和Fis1以及线粒体未折叠蛋白反应（UPRmt）因子LONP1和HSP60的mRNA水平。此外，PYR处理激活Keap1/Nrf2途径并上调HO-1和NQO-1，这减轻了氧化损伤，如8-OHDG降低所示，MDA和H2O2水平，并增加SOD活性。最后,PYR通过抑制AChE升高乙酰胆碱（ACh）水平，并上调HFD喂养小鼠的α7nAChR和M3AChR蛋白。PYR通过α7nAChR和M3AChR减轻线粒体损伤和氧化应激，减轻肥胖诱导的小鼠肝损伤。
