General ICU, The First Affiliated Hospital of Zhengzhou University, Henan Key Laboratory of Critical Care Medicine, Zhengzhou Key Laboratory of Sepsis, Henan Engineering Research Center for Critical Care Medicine, Zhengzhou, China.
Academy of Medical Sciences, Zhengzhou University, Zhengzhou, China.
Bioengineered. 2022 Feb;13(2):4598-4609. doi: 10.1080/21655979.2022.2036305.
Sepsis-associated liver injury is with poor survival in intensive care units. Metformin is well known for its therapeutic effects; however, its impact on treating liver injury due to sepsis remains poorly understood. This study investigated the therapeutic effects of metformin on aged mice suffering from sepsis-associated liver injury. Male C57BL/6 J mice aged (18-19 months) were divided into 3 groups: 1) intraperitoneal injection of sterile normal saline (C group), 12.5 mg/kg lipopolysaccharide (LPS) to induce sepsis-associated liver injury (LPS group), and 25 mg/kg metformin (MET) at 1 h after LPS injection (MET group). After 24 h, blood samples and liver tissue were collected for biochemical analysis. Histological assays revealed significantly elevated inflammatory infiltration and apoptosis in the liver, while metformin was found to relieve these aberrant features. The percentage of apoptotic cells decreased after metformin treatment ( < 0.05). Additionally, MET group had significantly reduced plasma alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels compared to the LPS group ( < 0.05). Furthermore, in the MET group, the mRNA levels of chemokines and inflammatory factors, TNF-α, IL-6, caspase-1, decreased markedly ( < 0.05). Metformin notably reversed the decreased phosphorylated AMP-activated protein kinase (p-AMPK) and PGC-1α expressions in the liver of septic rats. Metformin also inhibited PDK1, HIF-1α expression, including downstream inflammatory mediators, HMGB1 and TNF-α. Metformin attenuated inflammation and liver injury in septic aged mice. Most importantly, we report the effect of metformin on liver injury via the AMPK-PGC1α axis in septic aged mice for the first time.
脓毒症相关性肝损伤患者在重症监护病房的生存率较差。二甲双胍以其治疗效果而闻名；然而，其对治疗脓毒症相关性肝损伤的影响仍知之甚少。本研究旨在探讨二甲双胍对脓毒症相关性肝损伤老年小鼠的治疗作用。雄性 C57BL/6J 小鼠（18-19 月龄）分为 3 组：1）腹腔注射无菌生理盐水（C 组），12.5mg/kg 脂多糖（LPS）诱导脓毒症相关性肝损伤（LPS 组），25mg/kg 二甲双胍（MET）在 LPS 注射后 1h（MET 组）。24h 后，采集血样和肝组织进行生化分析。组织学检测显示，肝脏炎症浸润和细胞凋亡明显增加，而二甲双胍可缓解这些异常特征。二甲双胍治疗后凋亡细胞比例下降（ < 0.05）。此外，MET 组血浆丙氨酸氨基转移酶（ALT）和天冬氨酸氨基转移酶（AST）水平明显低于 LPS 组（ < 0.05）。此外，MET 组趋化因子和炎症因子 TNF-α、IL-6、caspase-1 的 mRNA 水平显著降低（ < 0.05）。二甲双胍显著逆转了脓毒症大鼠肝脏中磷酸化 AMP 激活蛋白激酶（p-AMPK）和 PGC-1α表达的降低。二甲双胍还抑制 PDK1、HIF-1α表达，包括下游炎症介质 HMGB1 和 TNF-α。二甲双胍减轻了老年脓毒症小鼠的炎症和肝损伤。最重要的是，我们首次报道了二甲双胍通过 AMPK-PGC1α 轴对老年脓毒症小鼠肝损伤的作用。
