Tang Xiaomeng, Ning Jingjing, Zhao Yilin, Feng Shuyun, Shao Lujing, Liu Tiantian, Miao Huijie, Zhang Yucai, Wang Chunxia
Department of Critical Care Medicine, Shanghai Children's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
Laboratory of Critical Care Translational Medicine, Institute of Pediatric Infection, Immunity, and Critical Care Medicine, Shanghai Children's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
J Intensive Med. 2024 Oct 10;5(1):79-88. doi: 10.1016/j.jointm.2024.06.003. eCollection 2025 Jan.
Cholestasis plays a critical role in sepsis-associated liver injury (SALI). Intestine-derived fibroblast growth factor 19 (FGF19) is a key regulator for bile acid homeostasis. However, the roles and underlying mechanisms of FGF19 in SALI are still unclear.
We conducted a case-control study that included 58 pediatric patients aged from 1 month to 14-years-old diagnosed with sepsis at Shanghai Children's Hospital from January to December 2018 and 30 healthy individuals. The serum FGF19 levels of these patients with sepsis were analyzed and compared with those of healthy controls. Recombinant human FGF19 was intravenously injected in mice once a day for 7 days at a dose of 0.1 mg/kg body weight before lipopolysaccharide (LPS) treatment. Liver bile acid profiles and the gene expression involved in bile acid homeostasis were investigated in the mice groups. Metabolomic data were further integrated and analyzed using Ingenuity Pathways Analysis (IPA) software. In the analysis using HepG2 cells, the influence of FGF19 pretreatment on reactive oxygen species (ROS) production and mitochondrial dysfunction was analyzed. Compound C (CC), an inhibitor of AMP-activated protein kinase (AMPK) activation, was used to confirm the roles of AMPK activation in FGF19-mediated hepatoprotective effects.
Serum FGF19 levels were significantly lower in children with sepsis than in healthy controls (115 pg/mL . 79 pg/mL, =0.03). Pre-administration of recombinant human FGF19 alleviated LPS-induced acute liver injury (ALI) and improved LPS-induced cholestasis in mice. Moreover, FGF19 directly reversed LPS-induced intracellular ROS generation and LPS-decreased mitochondrial membrane potential and , resulting in hepatoprotection against LPS-induced apoptosis. More importantly, the inhibition of AMPK activity partially blocked the protective effects of FGF19 against LPS-induced oxidative stress and mitochondrial dysfunction.
Intestine-derived FGF19 alleviates LPS-induced ALI via improving bile acid homeostasis and directly suppressing ROS production via activating the AMPK signaling pathway.
胆汁淤积在脓毒症相关肝损伤（SALI）中起关键作用。肠源成纤维细胞生长因子19（FGF19）是胆汁酸稳态的关键调节因子。然而，FGF19在SALI中的作用及潜在机制仍不清楚。
我们进行了一项病例对照研究，纳入了2018年1月至12月在上海儿童医学中心诊断为脓毒症的58例1个月至14岁的儿科患者以及30名健康个体。分析这些脓毒症患者的血清FGF19水平，并与健康对照者进行比较。在脂多糖（LPS）处理前，以0.1mg/kg体重的剂量每天一次给小鼠静脉注射重组人FGF19，共7天。研究小鼠组的肝脏胆汁酸谱以及参与胆汁酸稳态的基因表达。使用Ingenuity Pathways Analysis（IPA）软件进一步整合和分析代谢组学数据。在使用HepG2细胞的分析中，分析FGF19预处理对活性氧（ROS）产生和线粒体功能障碍的影响。使用AMP激活的蛋白激酶（AMPK）激活抑制剂化合物C（CC）来确认AMPK激活在FGF19介导的肝保护作用中的作用。
脓毒症患儿的血清FGF19水平显著低于健康对照者（115 pg/mL比79 pg/mL，P=0.03）。预先给予重组人FGF19可减轻LPS诱导的小鼠急性肝损伤（ALI），并改善LPS诱导的胆汁淤积。此外，FGF19直接逆转LPS诱导的细胞内ROS生成以及LPS降低的线粒体膜电位ΔΨm和ATP水平，从而对LPS诱导的细胞凋亡产生肝保护作用。更重要的是，抑制AMPK活性部分阻断了FGF19对LPS诱导的氧化应激和线粒体功能障碍的保护作用。
肠源FGF19通过改善胆汁酸稳态并通过激活AMPK信号通路直接抑制ROS产生，从而减轻LPS诱导的ALI。
