Serum metabolomic profiling in acute alcoholic hepatitis identifies multiple dysregulated pathways.
Serum metabolomic profiling in acute alcoholic hepatitis identifies multiple dysregulated pathways.
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DOI：
10.1371/journal.pone.0113860
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Behari J
中科院分区：
文献类型：
--
作者：
Rachakonda V;Gabbert C;Raina A;Bell LN;Cooper S;Malik S;Behari J
虽然动物研究表明全球能量平衡失调与急性酒精性肝炎(AAH)的发病机制有关，但这些发现与人类AAH的发生发展之间的相关性仍不清楚。利用全球、无偏倚的血清代谢组学分析，我们试图描述与严重AAH相关的代谢途径的变化，并确定潜在的疾病预后生物标志物。这项前瞻性病例对照研究设计包括25名重度AAH患者和25名酒精性肝硬变患者。在指标临床相遇后24小时内采集血清样本。进行了全面的、无偏倚的代谢组学分析。在登记后对患者进行180天的跟踪调查，以确定存活率。严重AAH患者体内234种生物化学物质的水平发生了变化。随机森林分析、主成分分析和综合层次聚类方法表明，代谢组学特征区分两个队列的准确率为100%。重度AAH与甘油三酯脂解增强、线粒体脂肪酸β氧化受损和omega氧化上调相关。多种溶脂及相关代谢物水平低提示重度AAH患者质膜重塑减少。虽然大多数检测到的胆汁酸在重度AAH时升高，但低水平的脱氧胆酸和甘油脱氧胆酸水平表明肠道生物失调。在重度AAH中，能量平衡的底物利用发生了几个变化，包括磷酸戊糖途径增加的葡萄糖消耗，三羧酸(TCA)循环活性的改变，以及多肽分解代谢的增强。最后，在重度AAH患者中观察到与谷胱甘肽代谢相关的小分子水平的改变和抗氧化性维生素的枯竭。单因素Logistic回归分析显示，15种代谢物与重度AAH患者的180天存活期有关。重症AAH的特点是具有跨越多个途径的不同代谢表型。代谢组学分析揭示了一组疾病预后的生物标志物，未来的研究计划在更大规模的重度AAH患者队列中验证这些发现。
While animal studies have implicated derangements of global energy homeostasis in the pathogenesis of acute alcoholic hepatitis (AAH), the relevance of these findings to the development of human AAH remains unclear. Using global, unbiased serum metabolomics analysis, we sought to characterize alterations in metabolic pathways associated with severe AAH and identify potential biomarkers for disease prognosis. This prospective, case-control study design included 25 patients with severe AAH and 25 ambulatory patients with alcoholic cirrhosis. Serum samples were collected within 24 hours of the index clinical encounter. Global, unbiased metabolomics profiling was performed. Patients were followed for 180 days after enrollment to determine survival. Levels of 234 biochemicals were altered in subjects with severe AAH. Random-forest analysis, principal component analysis, and integrated hierarchical clustering methods demonstrated that metabolomics profiles separated the two cohorts with 100% accuracy. Severe AAH was associated with enhanced triglyceride lipolysis, impaired mitochondrial fatty acid beta oxidation, and upregulated omega oxidation. Low levels of multiple lysolipids and related metabolites suggested decreased plasma membrane remodeling in severe AAH. While most measured bile acids were increased in severe AAH, low deoxycholate and glycodeoxycholate levels indicated intestinal dysbiosis. Several changes in substrate utilization for energy homeostasis were identified in severe AAH, including increased glucose consumption by the pentose phosphate pathway, altered tricarboxylic acid (TCA) cycle activity, and enhanced peptide catabolism. Finally, altered levels of small molecules related to glutathione metabolism and antioxidant vitamin depletion were observed in patients with severe AAH. Univariable logistic regression revealed 15 metabolites associated with 180-day survival in severe AAH. Severe AAH is characterized by a distinct metabolic phenotype spanning multiple pathways. Metabolomics profiling revealed a panel of biomarkers for disease prognosis, and future studies are planned to validate these findings in larger cohorts of patients with severe AAH.
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影响因子：
2.3
作者：
Crabb, DW;Galli, A;You, M
通讯作者：
You, M
影响因子：
29.4
作者：
Mathurin, P;Duchatelle, V;Poynard, T
通讯作者：
Poynard, T
酒精性肝病：发病机制和新的治疗靶点。
影响因子：
29.4
作者：
Gao B;Bataller R
通讯作者：
Bataller R
影响因子：
9.8
作者：
Kalhan, Satish C.;Guo, Lining;Edmison, John;Dasarathy, Srinivasan;McCullough, Arthur J.;Hanson, Richard W.;Milburn, Mike
通讯作者：
Milburn, Mike
影响因子：
13.5
作者：
Dunn, W;Jamil, LH;Shah, V
通讯作者：
Shah, V