Switching from Fatty Acid Oxidation to Glycolysis Improves the Outcome of Acute‐On‐Chronic Liver Failure
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 hypox...
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Format: | Article |
Language: | English |
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Wiley
2020-04-01
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Series: | Advanced Science |
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Online Access: | https://doi.org/10.1002/advs.201902996 |
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doaj-5811c5313d63476293fb46d3a4f26143 |
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record_format |
Article |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Zujiang Yu Jingjing Li Zhigang Ren Ranran Sun Yang Zhou Qi Zhang Qiongye Wang Guangying Cui Juan Li Ang Li Zhenfeng Duan Yuming Xu Zhichao Wang Peiyuan Yin Hailong Piao Jun Lv Xiaorui Liu Yanfang Wang Ming Fang Zhengping Zhuang Guowang Xu Quancheng Kan |
spellingShingle |
Zujiang Yu Jingjing Li Zhigang Ren Ranran Sun Yang Zhou Qi Zhang Qiongye Wang Guangying Cui Juan Li Ang Li Zhenfeng Duan Yuming Xu Zhichao Wang Peiyuan Yin Hailong Piao Jun Lv Xiaorui Liu Yanfang Wang Ming Fang Zhengping Zhuang Guowang Xu Quancheng Kan Switching from Fatty Acid Oxidation to Glycolysis Improves the Outcome of Acute‐On‐Chronic Liver Failure Advanced Science acute‐on‐chronic liver failure hepatocytes hypoxia metabolic reprogramming |
author_facet |
Zujiang Yu Jingjing Li Zhigang Ren Ranran Sun Yang Zhou Qi Zhang Qiongye Wang Guangying Cui Juan Li Ang Li Zhenfeng Duan Yuming Xu Zhichao Wang Peiyuan Yin Hailong Piao Jun Lv Xiaorui Liu Yanfang Wang Ming Fang Zhengping Zhuang Guowang Xu Quancheng Kan |
author_sort |
Zujiang Yu |
title |
Switching from Fatty Acid Oxidation to Glycolysis Improves the Outcome of Acute‐On‐Chronic Liver Failure |
title_short |
Switching from Fatty Acid Oxidation to Glycolysis Improves the Outcome of Acute‐On‐Chronic Liver Failure |
title_full |
Switching from Fatty Acid Oxidation to Glycolysis Improves the Outcome of Acute‐On‐Chronic Liver Failure |
title_fullStr |
Switching from Fatty Acid Oxidation to Glycolysis Improves the Outcome of Acute‐On‐Chronic Liver Failure |
title_full_unstemmed |
Switching from Fatty Acid Oxidation to Glycolysis Improves the Outcome of Acute‐On‐Chronic Liver Failure |
title_sort |
switching from fatty acid oxidation to glycolysis improves the outcome of acute‐on‐chronic liver failure |
publisher |
Wiley |
series |
Advanced Science |
issn |
2198-3844 |
publishDate |
2020-04-01 |
description |
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. |
topic |
acute‐on‐chronic liver failure hepatocytes hypoxia metabolic reprogramming |
url |
https://doi.org/10.1002/advs.201902996 |
work_keys_str_mv |
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doaj-5811c5313d63476293fb46d3a4f261432020-11-25T03:19:25ZengWileyAdvanced Science2198-38442020-04-0177n/an/a10.1002/advs.201902996Switching from Fatty Acid Oxidation to Glycolysis Improves the Outcome of Acute‐On‐Chronic Liver FailureZujiang Yu0Jingjing Li1Zhigang Ren2Ranran Sun3Yang Zhou4Qi Zhang5Qiongye Wang6Guangying Cui7Juan Li8Ang Li9Zhenfeng Duan10Yuming Xu11Zhichao Wang12Peiyuan Yin13Hailong Piao14Jun Lv15Xiaorui Liu16Yanfang Wang17Ming Fang18Zhengping Zhuang19Guowang Xu20Quancheng Kan21Department of Infectious Disease The First Affiliated Hospital of Zhengzhou University Zhengzhou 450052 ChinaDepartment of Infectious Disease The First Affiliated Hospital of Zhengzhou University Zhengzhou 450052 ChinaDepartment of Infectious Disease The First Affiliated Hospital of Zhengzhou University Zhengzhou 450052 ChinaDepartment of Infectious Disease The First Affiliated Hospital of Zhengzhou University Zhengzhou 450052 ChinaCAS Key Laboratory of Separation Science for Analytical Chemistry Dalian Institute of Chemical Physics Chinese Academy of Sciences Dalian 116023 ChinaNeuro‐Oncology Branch Center for Cancer Research National Cancer Institute National Institutes of Health Bethesda MD 20892 USADepartment of Infectious Disease The First Affiliated Hospital of Zhengzhou University Zhengzhou 450052 ChinaDepartment of Infectious Disease The First Affiliated Hospital of Zhengzhou University Zhengzhou 450052 ChinaDepartment of Infectious Disease The First Affiliated Hospital of Zhengzhou University Zhengzhou 450052 ChinaDepartment of Infectious Disease The First Affiliated Hospital of Zhengzhou University Zhengzhou 450052 ChinaSarcoma Biology Laboratory Department of Orthopaedic Surgery Massachusetts General Hospital and Harvard Medical School Boston MA 02215 USADepartment of Pharmacy The First Affiliated Hospital of Zhengzhou University Zhengzhou 450052 ChinaCAS Key Laboratory of Separation Science for Analytical Chemistry Dalian Institute of Chemical Physics Chinese Academy of Sciences Dalian 116023 ChinaCAS Key Laboratory of Separation Science for Analytical Chemistry Dalian Institute of Chemical Physics Chinese Academy of Sciences Dalian 116023 ChinaScientific Research Center for Translational Medicine Dalian Institute of Chemical Physics Chinese Academy of Sciences Dalian 116023 ChinaDepartment of Infectious Disease The First Affiliated Hospital of Zhengzhou University Zhengzhou 450052 ChinaDepartment of Infectious Disease The First Affiliated Hospital of Zhengzhou University Zhengzhou 450052 ChinaDepartment of Pharmacy The First Affiliated Hospital of Zhengzhou University Zhengzhou 450052 ChinaMing Fang MD Inc. Walnut Creek CA 94596 USANeuro‐Oncology Branch Center for Cancer Research National Cancer Institute National Institutes of Health Bethesda MD 20892 USACAS Key Laboratory of Separation Science for Analytical Chemistry Dalian Institute of Chemical Physics Chinese Academy of Sciences Dalian 116023 ChinaDepartment of Pharmacy The First Affiliated Hospital of Zhengzhou University Zhengzhou 450052 ChinaAbstract 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.https://doi.org/10.1002/advs.201902996acute‐on‐chronic liver failurehepatocyteshypoxiametabolic reprogramming |