Data_Sheet_1_Metabonomic Profile of Macrosteatotic Allografts for Orthotopic Liver Transplantation in Patients With Initial Poor Function: Mechanistic Investigation and Prognostic Prediction.docx

BackgroundOur previous study revealled amplified hazardous effects of macrosteatosis (MaS) on graft failure (GF) in recipients with severe liver damage in short post-operative days, with vague mechanism inside.
AimWe aimed to uncover the molecular mechanism of donor MaS on GF, and construct the predictive model to monitor post-transplant prognosis based on “omics” perspective.
MethodsUltra-performance liquid chromatography coupled to mass spectrometry metabolomic analysis was performed in allograft tissues from 82 patients with initial poor function (IPF) from multi-liver transplant (LT) centers. Pathway analysis was performed by on-line toolkit Metaboanalyst (v 3.0). Predictive model was constructed based on combinative metabonomic and clinical data extracted by stepwised cox proportional analysis.
ResultsPrinciple component analysis (PCA) analysis revealled stratification on metabolic feature in organs classified by MaS status. Differential metabolits both associated with MaS and GF were significantly enriched on pathway of glycerophospholipid metabolism (P < 0.05). Phosphatidylcholine (PC) and phosphatidylethanolamine (PE) involved in glycerophospholipid metabolism was significantly decreased in cases with MaS donors and GF (P < 0.05). Better prediction was observed on graft survival by combinative model (area under the curve = 0.91) and confirmed by internal validation.
ConclusionMetabonomic features of allografts can be clearly distinguished by MaS status in patients with IPF. Dysfunction on glycerophospholipid metabolism was culprit to link donor MaS and final GF. Decrement on PC and PE exerted the fatal effects of MaS on organ failure. Metabonomic data might help for monitoring long-term graft survival after LT.

背景 本团队既往研究显示，在术后早期肝损伤严重的受者中，大泡性脂肪肝（macrosteatosis, MaS）对移植物功能衰竭（graft failure, GF）的有害影响被加剧，但其内在分子机制仍不明朗。
研究目的 本研究旨在阐明供者大泡性脂肪肝影响移植物功能衰竭的分子机制，并从组学（omics）视角构建可用于监测移植术后预后的预测模型。
研究方法 本研究纳入多中心肝移植（liver transplant, LT）中心的82例初始肝功能不良（initial poor function, IPF）受者的移植肝组织，采用超高效液相色谱-质谱联用技术开展代谢组学分析。通过在线工具Metaboanalyst（版本3.0）进行通路富集分析。基于逐步Cox比例风险分析提取的代谢组学与临床联合数据，构建预测模型。
研究结果 主成分分析（principal component analysis, PCA）结果显示，按供者大泡性脂肪肝状态分组的移植肝，其代谢特征存在显著分层。与大泡性脂肪肝及移植物功能衰竭均相关的差异代谢物，显著富集于甘油磷脂代谢通路（P < 0.05）。参与甘油磷脂代谢的磷脂酰胆碱（phosphatidylcholine, PC）与磷脂酰乙醇胺（phosphatidylethanolamine, PE），在供者存在大泡性脂肪肝且发生移植物功能衰竭的病例中显著下调（P < 0.05）。联合模型对移植物存活的预测效能更佳，曲线下面积（area under the curve, AUC）达0.91，并通过内部验证得到证实。
研究结论 对于初始肝功能不良受者，可根据供者大泡性脂肪肝状态清晰区分移植肝的代谢组学特征。甘油磷脂代谢功能异常是连接供者大泡性脂肪肝与最终移植物功能衰竭的核心机制。磷脂酰胆碱与磷脂酰乙醇胺的水平下调，介导了大泡性脂肪肝对器官衰竭的致命影响。代谢组学数据或可助力肝移植术后移植物长期存活的监测。