Affiliation:
1. Department of Pharmacy The Affiliated Hospital of Northwest University Xi'an China
2. The College of Life Sciences Northwest University Xi'an China
Abstract
AbstractObesity 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 H2O2 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.