Department of Pediatric Surgery, Xin Hua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China; Division of Pediatric Gastroenterology and Nutrition, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China; Shanghai Institute of Pediatric Research, Shanghai, China; Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai, China.
Department of Pediatric Surgery, Xin Hua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China; Shanghai Key Laboratory of Pediatric Gastroenterology and Nutrition, Shanghai, China.
Eur J Pharmacol. 2024 Mar 5;966:176334. doi: 10.1016/j.ejphar.2024.176334. Epub 2024 Jan 28.
Hyperammonemia refers to elevated levels of ammonia in the blood, which is an important pathological feature of liver cirrhosis and hepatic failure. Preclinical studies suggest tropifexor (TXR), a novel non-bile acid agonist of Farnesoid X Receptor (FXR), has shown promising effects on reducing hepatic steatosis, inflammation, and fibrosis. This study evaluates the impact of TXR on hyperammonemia in a piglet model of cholestasis. We here observed blood ammonia significantly elevated in patients with biliary atresia (BA) and was positively correlated with liver injury. Targeted metabolomics and immunblotting showed glutamine metabolism and urea cycles were impaired in BA patients. Next, we observed that TXR potently suppresses bile duct ligation (BDL)-induced injuries in liver and brain with improving the glutamine metabolism and urea cycles. Within the liver, TXR enhances glutamine metabolism and urea cycles by up-regulation of key regulatory enzymes, including glutamine synthetase (GS), carbamoyl-phosphate synthetase 1 (CPS1), argininosuccinate synthetase (ASS1), argininosuccinate lyase (ASL), and arginase 1 (ARG1). In primary mice hepatocytes, TXR detoxified ammonia via increasing ureagenesis. Mechanically, TXR activating FXR to increase express enzymes that regulating ureagenesis and glutamine synthesis through a transcriptional approach. Together, these results suggest that TXR may have therapeutic implications for hyperammonemic conditions in cholestatic livers.
高氨血症是指血液中氨水平升高，这是肝硬化和肝衰竭的重要病理特征。临床前研究表明，新型法尼醇 X 受体（FXR）非胆汁酸激动剂替西瑞韦（TXR）在降低肝脂肪变性、炎症和纤维化方面显示出良好的效果。本研究评估了 TXR 对胆汁淤积仔猪模型高氨血症的影响。我们观察到胆道闭锁（BA）患者的血液氨明显升高，且与肝损伤呈正相关。靶向代谢组学和免疫印迹显示 BA 患者谷氨酰胺代谢和尿素循环受损。接下来，我们观察到 TXR 可通过增强谷氨酰胺代谢和尿素循环来强力抑制胆管结扎（BDL）引起的肝和脑损伤。在肝脏中，TXR 通过上调关键调节酶，包括谷氨酰胺合成酶（GS）、磷酸鸟氨酸合成酶 1（CPS1）、精氨酸合成酶 1（ASS1）、精氨酸琥珀酸裂解酶（ASL）和精氨酸酶 1（ARG1），增强谷氨酰胺代谢和尿素循环。在原代小鼠肝细胞中，TXR 通过增加尿素生成来解毒氨。在机制上，TXR 通过转录激活 FXR 增加调节尿素生成和谷氨酰胺合成的酶的表达。总之，这些结果表明，TXR 可能对胆汁淤积性肝脏中的高氨血症具有治疗意义。
