目的 探讨虎金方通过沉默信息调节因子 1（SIRT1）调节线粒体功能改善代谢相关脂肪性肝病（MAFLD） 的机制。方法 采用高脂饲料喂养建立 MAFLD 小鼠模型。将小鼠随机分为正常组、模型组、虎金方低剂量组 （5.31 g·kg-1 ）、虎金方高剂量组（21.24 g·kg-1 ）、水飞蓟宾组（12 mg·kg-1 ）、EX-527 组（10 mg·kg-1 ）、EX-527+虎 金方低剂量组、EX-527+虎金方高剂量组、EX-527+水飞蓟宾组。各治疗组连续灌胃 4 周；EX-527 每周注射 两次，连续 4 周。记录小鼠体质量、肝质量；观察肝组织 HE 染色、油红 O 染色情况；检测血清甘油三酯 （TG）、总胆固醇（TC）、低密度脂蛋白胆固醇（LDL-C）、高密度脂蛋白胆固醇（HDL-C）、天冬氨酸氨基转移酶 （AST）、丙氨酸氨基转移酶（ALT）、肿瘤坏死因子 α（TNF-α）、白细胞介素 6（IL-6）水平；检测肝组织丙二醛 （MDA）、超氧化物歧化酶（SOD）、活性氧（ROS）、三磷酸腺苷（ATP）含量；采用 Western Blot 法检测肝组织 SIRT1、过氧化物酶体增殖物激活受体 γ 共激活因子 1α（PGC-1α）、核呼吸因子 1（NRF1）、线粒体转录因子 A （TFAM）蛋白表达水平。结果 与正常组比较，模型组小鼠体质量、肝质量显著增加（P＜0.01）；肝组织结构紊 乱，脂肪空泡增多；TG、TC、LDL-C、AST、ALT、TNF-α、IL-6、MDA 水平显著升高（P＜0.000 1），ATP 含 量显著降低（P＜0.000 1），SIRT1、PGC-1α、NRF1、TFAM 蛋白表达显著下调（P＜0.000 1）。与模型组比较， 治疗组小鼠体质量、肝质量显著降低（P＜0.01，P＜0.001，P＜0.000 1）；肝组织结构趋于正常，脂肪空泡数量 减少；TG、TC、LDL-C、AST、ALT、TNF-α、IL-6、MDA 水平显著降低（P＜0.05，P＜0.01，P＜0.001，P＜ 0.000 1），ATP 含量显著升高（P＜0.01，P＜0.001），SIRT1、PGC-1α、NRF1、TFAM 蛋白表达显著上调（P＜ 0.05，P＜0.01，P＜0.001，P＜0.000 1），且虎金方组呈一定量效关系。与模型组比较，EX-527 组（SIRT1 抑制 剂组）小鼠肝组织结构更为紊乱，脂肪空泡进一步增大、增多，红染现象更为严重；TNF-α、IL-6、MDA 水平 显著升高（P＜0.05，P＜0.000 1），ATP 含量显著降低（P＜0.000 1），SIRT1 蛋白表达显著下调（P＜0.000 1）。与 EX-527 组比较，EX-527+虎金方低剂量组、EX-527+虎金方高剂量组、EX-527+水飞蓟宾组小鼠体质量、肝 质量显著降低（P＜0.01，P＜0.001）；肝细胞排列较整齐，脂肪空泡数量明显减少；TG、TC、TNF-α、IL-6、 MDA 水平显著降低（P＜0.05，P＜0.01，P＜0.001），ATP 含量显著升高（P＜0.000 1）；EX-527+虎金方高剂量 组、EX-527+水飞蓟宾组 SIRT1 蛋白表达显著上调（P＜0.05）。结论 虎金方可能通过上调 SIRT1 改善肝脏线 粒体功能，促进脂质代谢，减轻肝脏炎症和氧化应激，从而延缓 MAFLD 进展。

Objective To investigate the mechanism by which Hujin Formula improves metabolic-associated fatty liver disease （MAFLD） by regulating mitochondrial function through silent information regulator 1（SIRT1）. Methods A MAFLD mouse model was established using a high-fat diet. The mice were randomly divided into a normal group，a model group，a low-dose Hujin Formula group （5.31 g·kg-1 ），a high-dose Hujin Formula group （21.24 g·kg-1 ），a Silibinin group （12 mg·kg-1 ），an EX-527 group （10 mg·kg-1 ），an EX-527 + low-dose Hujin Formula group，an EX-527 + high-dose Hujin Formula group，and an EX-527 + Silibinin group. The treatment groups were administered by gavage for 4 weeks，while EX-527 was injected twice weekly for 4 weeks. Body mass and liver mass were recorded. Liver tissue was observed using HE staining and Oil Red O staining. Serum levels of triglycerides （TG）， total cholesterol （TC）， low-density lipoprotein cholesterol （LDL-C）， high-density lipoprotein cholesterol （HDL-C）， aspartate aminotransferase （AST）， alanine aminotransferase （ALT）， tumor necrosis factor- α （TNF- α）， and interleukin-6（IL-6） were measured. The levels of malondialdehyde （MDA），superoxide dismutase （SOD），reactive oxygen species （ROS）， and adenosine triphosphate （ATP） in liver tissue were detected. Western Blot was used to measure the protein expression levels of SIRT1， peroxisome proliferator-activated receptor gamma coactivator-1α （PGC-1α），nuclear respiratory factor 1（NRF1），and transcription factor A，mitochondrial （TFAM） in liver tissue. Results Compared with the normal group，the model group showed significantly increased body mass and liver mass （P＜0.01），disordered liver tissue structure，and increased fat vacuoles. Serum levels of TG，TC，LDL-C，AST， ALT，TNF-α，and IL-6，as well as MDA levels in liver tissue，were significantly elevated （P＜0.000 1），while ATP content was significantly reduced （P＜0.000 1）. Protein expression of SIRT1，PGC-1α，NRF1，and TFAM was significantly downregulated （P＜0.000 1）. Compared with the model group， treatment groups showed significantly reduced body mass and liver mass （P＜0.01， P＜0.001， P＜0.000 1）， improved liver tissue structure， and decreased fat vacuoles. Serum levels of TG，TC，LDL-C，AST，ALT，TNF-α，and IL-6，as well as MDA levels in liver tissue， were significantly reduced （P＜0.05， P＜0.01， P＜0.001， P＜0.000 1）， while ATP content was significantly increased （P＜0.01， P＜0.001）. Protein expression of SIRT1， PGC-1α， NRF1， and TFAM was significantly upregulated （P＜0.05，P＜0.01，P＜0.001，P＜0.000 1），with a dose-dependent effect observed in the Hujin Formula groups. Compared with the model group，the EX-527 group （SIRT1 inhibitor group） exhibited more disordered liver tissue structure，larger and more numerous fat vacuoles，and more severe red staining. TNF-α，IL-6， and MDA levels were significantly elevated （P＜0.05， P＜0.000 1）， ATP content was significantly reduced （P＜ 0.000 1），and protein expression of SIRT1 was significantly downregulated （P＜0.000 1）. Compared with the EX-527 group，the EX-527 + low-dose Hujin Formula group，EX-527 + high-dose Hujin Formula group，and EX-527 + Silibinin group showed significantly reduced body mass and liver mass （P＜0.01，P＜0.001），more orderly hepatocyte arrangement，and significantly fewer fat vacuoles. Serum levels of TG，TC，TNF- α，and IL-6，as well as MDA levels in liver tissue， were significantly reduced （P＜0.05， P＜0.01， P＜0.001）， while ATP content was significantly increased （P＜0.000 1）. SIRT1 protein expression was significantly upregulated in the EX-527 + highdose Hujin Formula group and EX-527 + Silibinin group （P＜0.05）. Conclusion Hujin Formula may improve mitochondrial function，promote lipid metabolism，and alleviate liver inflammation and oxidative stress by upregulating SIRT1，thereby delaying the progression of MAFLD.

R285.5

广东省自然科学基金项目（2022A1515012265）。