Nonalcoholic fatty liver disease (NAFLD) is an increasingly prevalent disease that is associated with multiple metabolic disturbances, yet the metabolic pathways underlying its progression are poorly understood. Here we studied metabolic pathways of the human liver across the full histological spectrum of NAFLD. We analyzed whole liver tissue transcriptomics and serum metabolomics data obtained from a large, prospectively enrolled cohort of 206 histologically characterized patients derived from the European NAFLD Registry and developed genome-scale metabolic models (GEMs) of human hepatocytes at different stages of NAFLD. We identified several metabolic signatures in the liver and blood of these patients, specifically highlighting the alteration of vitamins (A, E) and glycosphingolipids, and their link with complex glycosaminoglycans in advanced fibrosis. Furthermore, we derived GEMs and identified metabolic signatures of three common NAFLD-associated gene variants (PNPLA3, TM6SF2 and HSD17B13). The study demonstrates dysregulated liver metabolic pathways which may contribute to the progression of NAFLD.

中文翻译：

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人类肝脏的定量基因组规模分析揭示了进行性非酒精性脂肪性肝病中鞘糖脂途径的失调

非酒精性脂肪肝 (NAFLD) 是一种日益流行的疾病，与多种代谢紊乱有关，但对其进展的代谢途径知之甚少。在这里，我们研究了人类肝脏在整个 NAFLD 组织学谱中的代谢途径。我们分析了从来自欧洲 NAFLD 登记处的 206 名具有组织学特征的大型患者队列中获得的全肝组织转录组学和血清代谢组学数据，并开发了 NAFLD 不同阶段人类肝细胞的基因组规模代谢模型 (GEM)。我们在这些患者的肝脏和血液中确定了几种代谢特征，特别强调了维生素（A、E）和鞘糖脂的改变，以及它们与晚期纤维化中复杂糖胺聚糖的联系。此外，我们导出了 GEM 并确定了三种常见的 NAFLD 相关基因变异的代谢特征（PNPLA3、TM6SF2和HSD17B13）。该研究表明肝脏代谢途径失调，这可能有助于 NAFLD 的进展。