Yu Zujiang, Li Jingjing, Ren Zhigang, Sun Ranran, Zhou Yang, Zhang Qi, Wang Qiongye, Cui Guangying, Li Juan, Li Ang, Duan Zhenfeng, Xu Yuming, Wang Zhichao, Yin Peiyuan, Piao Hailong, Lv Jun, Liu Xiaorui, Wang Yanfang, Fang Ming, Zhuang Zhengping, Xu Guowang, Kan Quancheng
Department of Infectious Disease The First Affiliated Hospital of Zhengzhou University Zhengzhou 450052 China.
CAS Key Laboratory of Separation Science for Analytical Chemistry Dalian Institute of Chemical Physics Chinese Academy of Sciences Dalian 116023 China.
Adv Sci (Weinh). 2020 Feb 13;7(7):1902996. doi: 10.1002/advs.201902996. eCollection 2020 Apr.
Acute-on-chronic liver failure (ACLF) has a high mortality rate. Metabolic reprogramming is an important mechanism for cell survival. Herein, the metabolic patterns of ACLF patients are analyzed. An in vitro model of ACLF is established using Chang liver cells under hyperammonemia and hypoxia. A randomized clinical trial (ChiCTR-OPC-15006839) is performed with patients receiving -ornithine and -aspartate (LOLA) daily intravenously (LOLA group) and trimetazidine (TMZ) tid orally (TMZ group) based on conventional treatment (control group). The primary end point is 90-day overall survival, and overall survival is the secondary end point. By analyzing metabolic profiles in liver tissue samples from hepatitis B virus (HBV)-related ACLF patients and the controls, the metabolic characteristics of HBV-related ACLF patients are identified: inhibited glycolysis, tricarboxylic acid cycle and urea cycle, and enhanced fatty acid oxidation (FAO) and glutamine anaplerosis. These effects are mainly attributed to hyperammonemia and hypoxia. Further in vitro study reveals that switching from FAO to glycolysis could improve hepatocyte survival in the hyperammonemic and hypoxic microenvironment. Importantly, this randomized clinical trial confirms that inhibiting FAO using TMZ improves the prognosis of patients with HBV-related ACLF. In conclusion, this study provides a practical strategy for targeting metabolic reprogramming using TMZ to improve the survival of patients with HBV-related ACLF.
慢加急性肝衰竭（ACLF）死亡率很高。代谢重编程是细胞存活的重要机制。在此，对ACLF患者的代谢模式进行分析。在高氨血症和缺氧条件下，使用Chang肝细胞建立ACLF体外模型。进行一项随机临床试验（ChiCTR-OPC-15006839），患者在常规治疗基础上，一组每日静脉注射鸟氨酸和门冬氨酸（LOLA组），另一组每日口服曲美他嗪（TMZ组，每日三次），以常规治疗组作为对照。主要终点是90天总生存率，总生存率为次要终点。通过分析乙型肝炎病毒（HBV）相关ACLF患者和对照组肝组织样本中的代谢谱，确定了HBV相关ACLF患者的代谢特征：糖酵解、三羧酸循环和尿素循环受到抑制，脂肪酸氧化（FAO）和谷氨酰胺补充途径增强。这些影响主要归因于高氨血症和缺氧。进一步的体外研究表明，在高氨血症和缺氧微环境中，从FAO转换为糖酵解可以提高肝细胞存活率。重要的是，这项随机临床试验证实，使用TMZ抑制FAO可改善HBV相关ACLF患者的预后。总之，本研究提供了一种实用策略，即通过靶向代谢重编程使用TMZ来提高HBV相关ACLF患者的生存率。
