BACKGROUND Obesity can influence hepatic mitochondrial function, and cause non-alcoholic steatohepatitis (NASH). Diagnosis and follow-up rely on invasive liver biopsy so blood-based markers are urgently required. AIM To investigate whether values of circulating metabolites from energy and one-carbon (1-C) metabolism may: (a) reflect hepatic mitochondrial flexibility failure and (b) act as NASH biomarkers. METHODS Patients with severe obesity undergoing bariatric surgery (n = 270) were investigated using quantitative targeted plasma metabolomics. Comparisons were with non-obese controls without liver disease (n = 50). Obese patients with NASH (n = 53) and without NASH (n = 130) representing extreme groups of liver disease were assessed to test the diagnostic ability of the measured circulating metabolites. Paired liver biopsy and plasma samples from NASH patients were available 1 year post-surgery and were evaluated to monitor metabolomic changes with liver damage resolution. RESULTS We identified correlations between human liver metabolism and obesity. High-plasma α-ketoglutarate (α-KG) and lactate concentrations in NASH patients indicating citric acid cycle replenishment via glutaminolysis might also be a crucial point in NASH onset. Plasma measurements of α-KG, β-hydroxybutyrate, pyruvate and oxaloacetate reduced the uncertainty in clinical diagnosis of NASH [area under receiver operating characteristic curve (AUC) of 0.826] and predicted NASH resolution without ambiguity (AUC of 0.999). CONCLUSION Changes in plasma mitochondrial metabolites appear to be associated with NASH. These metabolic responses may be dynamically remodelled following resolution of liver damage through massive weight loss.

中文翻译：

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严重肥胖和非酒精性脂肪性肝炎患者的血浆代谢改变。

背景技术肥胖可影响肝线粒体功能，并引起非酒精性脂肪性肝炎（NASH）。诊断和随访依赖于侵入性肝活检，因此迫切需要基于血液的标记物。目的研究能量和单碳（1-C）代谢中循环代谢物的值是否可以：（a）反映肝线粒体柔性衰竭，以及（b）充当NASH生物标志物。方法采用定量靶向血浆代谢组学方法对肥胖症患者进行减肥手术（n = 270）进行了研究。与没有肝病的非肥胖对照组进行比较（n = 50）。评估了患有NASH（n = 53）和没有NASH（n = 130）代表极端肝病组的肥胖患者，以测试所测循环代谢物的诊断能力。手术后1年可获得成对的NASH患者的肝活检和血浆样本，并进行了评估以监测代谢组学变化与肝脏损害的关系。结果我们确定了人类肝脏代谢与肥胖之间的相关性。NASH患者中的高血浆α-酮戊二酸（α-KG）和乳酸盐浓度表明通过谷氨酰胺分解来补充柠檬酸循环也可能是NASH发作的关键点。血浆中α-KG，β-羟基丁酸酯，丙酮酸和草酰乙酸的测量降低了NASH临床诊断的不确定性（接受者工作特征曲线（AUC）为0.826的区域），并预测了NASH的分辨率而没有歧义（AUC为0.999）。结论血浆线粒体代谢产物的变化似乎与NASH有关。