Switching from Fatty Acid Oxidation to Glycolysis Improves the Outcome of Acute‐On‐Chronic Liver Failure. Issue 7 (13th February 2020)

• Record Type: Journal Article
• Authors: 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
• Is Part Of: Advanced science. Volume 7:Issue 7(2020)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2020-02-13
• Subjects: acute‐on‐chronic liver failure -- hepatocytes -- hypoxia -- metabolic reprogramming; Science -- Periodicals; 505
• DOI: 10.1002/advs.201902996
• Languages: English
• ISSNs: 2198-3844

Abstract

Abstract: 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 L ‐ornithine and L ‐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. Abstract : Metabolic characteristics are identified in patients with acute‐on‐chronic liver failure: inhibited glycolysis, tricarboxylic acid cycle (TAC) and urea cycle, and enhanced fatty acid oxidation (FAO) and glutamine anaplerosis. These effects are mainly attributed to hyperammonemia and hypoxia. Trimetazidine that is used to inhibit FAO could enhance glycolysis, TAC and urea cycle, but inhibit glutamine anaplerosis, thereby improving patients' survival.