Wang Jiahui, Ma Li, An Yuan, Ge Yan, Xu Dan, Mao Enqiang
Department of Emergency, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
Department of Orthopaedics, Shanghai Key Laboratory for Bone and Joint Diseases, Shanghai Institute of Traumatology and Orthopaedics, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
Pharmaceuticals (Basel). 2025 May 21;18(5):763. doi: 10.3390/ph18050763.
Abnormal bile acid (BA) pool may play an important role in inducing liver damage in sepsis. Farnesoid X receptor (FXR) is a main negative feedback regulator of BA metabolism. This study aims to explore the protective effect and mechanism of the FXR agonist obeticholic acid (OCA) on liver dysfunction when sepsis occurs. A rat model of sepsis was induced by cecal ligation and puncture (CLP) for 24 h. Systematic inflammation, tissue injury, hepatic FXR, and BA transporter expression were investigated in the CLP rats and sham-operated control rats with and without OCA pre-treatment (10 mg/kg, gavage) at 2 h before operation. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay was performed to access BA composition in the rats' serum and livers. The injury and inflammatory effects of the elevated unconjugated BAs found in the CLP rats was further verified in a hepatic cell line BRL-3A in vitro. Hepatic FXR was repressed in CLP rats, whereas OCA upregulated liver FXR and hepatic BA transporter expression, reduced total serum BA concentration, ameliorated the elevation of serum levels of IL-1β and IL-6, and improved liver and ileal tissue injuries. OCA administration reduced the elevated unconjugated BAs in both serum and liver, and effectively inhibited increases in cholic acid (CA), deoxycholic acid (DCA), and 7-ketoDCA concentrations in CLP rat livers. These BA fractions promoted the release of aspartate aminotransferase (AST) from BRL-3A cells and increased IL-6, CXCL2, and monocyte chemoattractant protein-1 (MCP-1) expression in the cells, along with enhanced transcription factor nuclear factor-κB activation. Liver inflammation and dysfunction during sepsis is attributable to significant changes in bile acid composition in the blood and liver. FXR activation reduces systemic inflammation and liver dysfunction by regulating bile acid homeostasis, especially inflammatory unconjugated bile acid components.
异常胆汁酸（BA）池可能在脓毒症诱导肝损伤中起重要作用。法尼酯X受体（FXR）是BA代谢的主要负反馈调节因子。本研究旨在探讨FXR激动剂奥贝胆酸（OCA）在脓毒症发生时对肝功能障碍的保护作用及机制。采用盲肠结扎和穿刺（CLP）法建立大鼠脓毒症模型24小时。在手术前2小时对CLP大鼠和假手术对照大鼠进行或不进行OCA预处理（10mg/kg，灌胃），研究全身炎症、组织损伤、肝脏FXR和BA转运体表达情况。采用液相色谱-串联质谱（LC-MS/MS）分析法检测大鼠血清和肝脏中的BA成分。在体外肝细胞系BRL-3A中进一步验证CLP大鼠中发现的未结合BA升高的损伤和炎症作用。CLP大鼠肝脏FXR被抑制，而OCA上调肝脏FXR和肝脏BA转运体表达，降低血清总BA浓度，改善血清IL-1β和IL-6水平升高，并改善肝脏和回肠组织损伤。给予OCA可降低血清和肝脏中升高的未结合BA，并有效抑制CLP大鼠肝脏中胆酸（CA）、脱氧胆酸（DCA）和7-酮脱氧胆酸（7-ketoDCA）浓度的升高。这些BA组分促进了天冬氨酸转氨酶（AST）从BRL-3A细胞的释放，并增加了细胞中IL-6、CXCL2和单核细胞趋化蛋白-1（MCP-1）的表达，同时增强了转录因子核因子-κB的激活。脓毒症期间的肝脏炎症和功能障碍归因于血液和肝脏中胆汁酸组成的显著变化。FXR激活通过调节胆汁酸稳态，特别是炎症性未结合胆汁酸成分，减轻全身炎症和肝脏功能障碍。
