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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 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.

SUBMITTER: Yu Z

PROVIDER: S-EPMC7141014 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

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Switching from Fatty Acid Oxidation to Glycolysis Improves the Outcome of Acute-On-Chronic Liver Failure.

Yu Zujiang Z Li Jingjing J Ren Zhigang Z Sun Ranran R Zhou Yang Y Zhang Qi Q Wang Qiongye Q Cui Guangying G Li Juan J Li Ang A Duan Zhenfeng Z Xu Yuming Y Wang Zhichao Z Yin Peiyuan P Piao Hailong H Lv Jun J Liu Xiaorui X Wang Yanfang Y Fang Ming M Zhuang Zhengping Z Xu Guowang G Kan Quancheng Q

Advanced science (Weinheim, Baden-Wurttemberg, Germany) 20200213 7

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 <i>L</i>-ornithine and <i>L</i>-aspartate (LOLA) daily intravenously (LOLA group) and trimetazidine (TMZ) tid orally ( ...[more]

PMID: 32274306

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Project description:BackgroundAlcohol is the leading cause of acute-on-chronic liver failure (ACLF). Several severity scores predict the outcome of ACLF. However, there is a lack of simple biomarkers in predicting the outcome of these sick patients. Fatty acid-binding proteins (FABPs) are small cytosolic proteins that play a major role in lipid metabolism, energy homeostasis, and inflammation, but, have not been investigated in alcohol-induced ACLF (A-ACLF).ObjectivesThe primary objective was to assess the correlation between serum adipocyte-FABP (A-FABP) and liver-FABP (L-FABP) levels on mortality at day 90. Secondary objectives were to compare the levels between controls and A-ACLF, correlate L-FABP, and A-FABP levels on the development of organ failure/sepsis at day 90.MethodsIn this prospective observational pilot study, we included patients with A-ACLF and age-matched healthy controls. FABP's were analyzed by enzyme-linked immunosorbent assay method. The patients were followed up for 90 days.ResultsTwenty-five patients with A-ACLF (mean age: 40years; mean model for end-stage liver disease NA: 29.8; median Modified Maddrey's discriminant function [mDF]: 95) and 12 controls (mean age: 36.83yrs) were included in the study. A-FABP and L-FABP levels were significantly high in patients with A-ACLF than controls. Forty-four percent of patients with A-ACLF developed sepsis, 48% developed organ failure, and 44% expired by day 90. On multivariate Cox regression analysis, A-FABP (hazard ratio [HR]: 1.27 [1.08-1.5]; P = 0.003), Asian Pacific Association for the Study of Liver ACLF research consortium score (HR: 3.3[1.15-9.54]; P = 0.02), L-FABP (HR: 0.69 [0.52-0.91]; P = 0.009), and serum protein levels (HR: 0.03 [0.003-0.36]; P = 0.005) predicted mortality. A-FABP (1.17 [1.07-1.29]; P = 0.001), and serum bilirubin (1.05 [0.99-1.12]; P = 0.06) predicted development of organ failure, and only mDF (HR: 1.04 [1.01-1.07]; P = 0.009) predicted the development of sepsis on multivariate analysis. Fifteen patients received steroid therapy, of which 13.34% were nonresponders.ConclusionsIn a selected group of patients with A-ACLF, A-FABP is highly sensitive at predicting mortality and outcome. If validated in a large, diverse sample, A-FABP can be used as a simple biomarker for prognostication in A-ACLF.

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Switching from Fatty Acid Oxidation to Glycolysis Improves the Outcome of Acute-On-Chronic Liver Failure.

Publications

Switching from Fatty Acid Oxidation to Glycolysis Improves the Outcome of Acute-On-Chronic Liver Failure.

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