Guangdong Metabolic Diseases Research Center of Integrated Chinese and Western MedicineGuangdong Pharmaceutical UniversityGuangzhouChina.
Institute of Chinese MedicineGuangdong Pharmaceutical UniversityGuangzhouChina.
Hepatology. 2021 Aug;74(2):686-703. doi: 10.1002/hep.31749.
Nonalcoholic fatty liver disease, especially nonalcoholic steatohepatitis (NASH), has become a major cause of liver transplantation and liver-associated death. NASH is the hepatic manifestation of metabolic syndrome and is characterized by hepatic steatosis, inflammation, hepatocellular injury, and different degrees of fibrosis. However, there is no US Food and Drug Administration-approved medication to treat this devastating disease. Therapeutic activators of the AMP-activated protein kinase (AMPK) have been proposed as a potential treatment for metabolic diseases such as NASH. Cordycepin, a natural product isolated from the traditional Chinese medicine Cordyceps militaris, has recently emerged as a promising drug candidate for metabolic diseases.
We evaluated the effects of cordycepin on lipid storage in hepatocytes, inflammation, and fibrosis development in mice with NASH. Cordycepin attenuated lipid accumulation, inflammation, and lipotoxicity in hepatocytes subjected to metabolic stress. In addition, cordycepin treatment significantly and dose-dependently decreased the elevated levels of serum aminotransferases in mice with diet-induced NASH. Furthermore, cordycepin treatment significantly reduced hepatic triglyceride accumulation, inflammatory cell infiltration, and hepatic fibrosis in mice. In vitro and in vivo mechanistic studies revealed that a key mechanism linking the protective effects of cordycepin were AMPK phosphorylation-dependent, as indicated by the finding that treatment with the AMPK inhibitor Compound C abrogated cordycepin-induced hepatoprotection in hepatocytes and mice with NASH.
Cordycepin exerts significant protective effects against hepatic steatosis, inflammation, liver injury, and fibrosis in mice under metabolic stress through activation of the AMPK signaling pathway. Cordycepin might be an AMPK activator that can be used for the treatment of NASH.
非酒精性脂肪性肝病，尤其是非酒精性脂肪性肝炎（NASH），已成为肝移植和与肝相关死亡的主要原因。NASH 是代谢综合征的肝脏表现，其特征为肝脂肪变性、炎症、肝细胞损伤和不同程度的纤维化。然而，目前尚无美国食品和药物管理局批准的药物可用于治疗这种毁灭性疾病。AMP 激活蛋白激酶（AMPK）的治疗激活剂已被提议作为治疗 NASH 等代谢疾病的潜在方法。从传统中药蛹虫草中分离得到的天然产物虫草素，最近已成为治疗代谢疾病的一种有前途的候选药物。
我们评估了虫草素对 NASH 小鼠肝细胞脂质储存、炎症和纤维化发展的影响。虫草素可减轻代谢应激状态下肝细胞中的脂质积累、炎症和脂毒性。此外，虫草素治疗可显著降低饮食诱导的 NASH 小鼠血清转氨酶的升高水平，并呈剂量依赖性。此外，虫草素治疗可显著减少 NASH 小鼠肝脏的甘油三酯积累、炎症细胞浸润和肝纤维化。体外和体内的机制研究表明，虫草素发挥保护作用的关键机制与 AMPK 磷酸化有关，因为 AMPK 抑制剂 Compound C 的处理消除了虫草素在肝细胞和 NASH 小鼠中诱导的肝保护作用。
虫草素通过激活 AMPK 信号通路，对代谢应激下的小鼠肝脂肪变性、炎症、肝损伤和纤维化具有显著的保护作用。虫草素可能是一种可用于治疗 NASH 的 AMPK 激活剂。
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