Metabolic signatures across the full spectrum of non-alcoholic fatty liver disease.
Metabolic signatures across the full spectrum of non-alcoholic fatty liver disease.
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非酒精性脂肪肝的代谢特征
DOI：
10.1016/j.jhepr.2022.100477
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发表时间：
2022-05
期刊：
影响因子：
8.3
通讯作者：
Oresic, Matej
中科院分区：
文献类型：
--
作者：
McGlinchey, Aidan J.;Govaere, Olivier;Geng, Dawei;Ratziu, Vlad;Allison, Michael;Bousier, Jerome;Petta, Salvatore;de Oliviera, Claudia;Bugianesi, Elisabetta;Schattenberg, Jorn M.;Daly, Ann K.;Hyotylainen, Tuulia;Anstee, Quentin M.;Oresic, Matej
非酒精性脂肪性肝病（NAFLD）是一种进行性肝病，具有潜在的严重并发症，包括肝硬化和肝细胞癌。以前，我们已经确定了与肝脏脂肪含量和非酒精性脂肪性肝炎（NASH）相关的循环脂质特征。在这里，我们开发了一个跨NAFLD谱的代谢组学图谱，定义了脂肪变性（非酒精性脂肪肝，NASH和纤维化）的相互关联的代谢特征。
我们对来自欧洲NAFLD登记患者（n = 627）的血清样本中的分子脂质和极性代谢物进行了质谱分析，代表了NAFLD的全部谱。使用各种单变量、多变量和机器学习统计方法，我们从3个临床角度研究了代谢物：脂肪变性、NASH和纤维化。
在NAFLD代谢网络生成后，我们确定了脂肪变性特有的15种代谢物，NASH特有的18种代谢物，纤维化特有的15种代谢物，其中27种是所有代谢物共有的。我们发现，从F2到F3纤维化的进展与疾病自然史中的关键病理生理学转变点一致，n = 73代谢物发生改变。
对循环代谢物的分析提供了对NAFLD进展期间代谢变化的重要见解，揭示了NAFLD谱中的代谢特征以及NAFL、NASH和纤维化的特异性特征。F2-F3转换标志着NAFLD发病机制中的关键代谢转换点，数据指向代谢应激和特别是氧化应激的病理生理学重要性。
该研究在Clinicaltrials.gov（NCT 04442334）上注册。
非酒精性脂肪性肝病的特征是肝脏中脂肪的积聚，其进展为肝功能障碍、瘢痕形成和不可逆的肝功能衰竭，并且其在全球范围内的患病率显著增加。在这里，我们测量了血液中的脂质和其他小分子（代谢物），目的是提供脂肪堆积，肝纤维化和诊断严重程度的全面分子概述。我们确定了肝损伤进展中的一个关键代谢“分水岭”，将严重疾病与轻度疾病区分开来，并表明特定的脂质和代谢产物谱可以帮助区分和/或定义这些病例。
我们在NAFLD的全谱范围内组建了一个高度表型化和特征化的NAFLD患者队列。
该数据集的脂质组学和代谢组学询问揭示了NAFLD在纤维化阶段F2-F3的关键代谢临界点。
纤维化、脂肪变性和NASH进展的NAFLD过程平行于代谢组学特征的不同变化。
肝脏通过醚脂质的氧化应激缓冲潜力似乎是晚期NASH过程中的关键变化之一。
Non-alcoholic fatty liver disease (NAFLD) is a progressive liver disease with potentially severe complications including cirrhosis and hepatocellular carcinoma. Previously, we have identified circulating lipid signatures associating with liver fat content and non-alcoholic steatohepatitis (NASH). Here, we develop a metabolomic map across the NAFLD spectrum, defining interconnected metabolic signatures of steatosis (non-alcoholic fatty liver, NASH, and fibrosis). We performed mass spectrometry analysis of molecular lipids and polar metabolites in serum samples from the European NAFLD Registry patients (n = 627), representing the full spectrum of NAFLD. Using various univariate, multivariate, and machine learning statistical approaches, we interrogated metabolites across 3 clinical perspectives: steatosis, NASH, and fibrosis. Following generation of the NAFLD metabolic network, we identify 15 metabolites unique to steatosis, 18 to NASH, and 15 to fibrosis, with 27 common to all. We identified that progression from F2 to F3 fibrosis coincides with a key pathophysiological transition point in disease natural history, with n = 73 metabolites altered. Analysis of circulating metabolites provides important insights into the metabolic changes during NAFLD progression, revealing metabolic signatures across the NAFLD spectrum and features that are specific to NAFL, NASH, and fibrosis. The F2–F3 transition marks a critical metabolic transition point in NAFLD pathogenesis, with the data pointing to the pathophysiological importance of metabolic stress and specifically oxidative stress. The study is registered at Clinicaltrials.gov (NCT04442334). Non-alcoholic fatty liver disease is characterised by the build-up of fat in the liver, which progresses to liver dysfunction, scarring, and irreversible liver failure, and is markedly increasing in its prevalence worldwide. Here, we measured lipids and other small molecules (metabolites) in the blood with the aim of providing a comprehensive molecular overview of fat build-up, liver fibrosis, and diagnosed severity. We identify a key metabolic ‘watershed’ in the progression of liver damage, separating severe disease from mild, and show that specific lipid and metabolite profiles can help distinguish and/or define these cases. We assembled a highly phenotyped and characterised cohort of patients with NAFLD across the full spectrum of NAFLD. Lipidomic and metabolomic interrogation of this dataset reveals crucial metabolic tipping point of NAFLD at fibrosis stage F2–F3. NAFLD processes of fibrosis, steatosis, and NASH progression parallel distinct changes in metabolomic profiles. Oxidative stress-buffering potential of the liver via ether lipids appears 1 of the key changes en route to late-stage NASH.
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影响因子：
7.7
作者：
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4.4
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作者：
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通讯作者：
Anstee, Quentin M.