Non-Alcoholic Fatty Liver Disease (NAFLD) is considered as the forthcoming predominant cause for hepatocellular carcinoma (HCC). NAFLD-HCC may rise in non-cirrhotic livers in 40 to 50% of patients. The aim of this study was to identify different metabolic pathways of HCC according to fibrosis level (F0F1 vs. F3F4). A non-targeted metabolomics strategy was applied. We analyzed 52 pairs of human HCC and adjacent non-tumoral tissues which included 26 HCC developed in severe fibrosis or cirrhosis (F3F4) and 26 in no or mild fibrosis (F0F1). Tissue extracts were analyzed using ¹H-Nuclear Magnetic Resonance spectroscopy. An optimization evolutionary method based on genetic algorithm was used to identify discriminant metabolites. We identified 34 metabolites differentiating the two groups of NAFLD-HCC according to fibrosis level, allowing us to propose two metabolomics phenotypes of NAFLD-HCC. We showed that HCC-F0F1 mainly overexpressed choline derivatives and glutamine, whereas HCC-F3F4 were characterized by a decreased content of monounsaturated fatty acids (FA), an increase of saturated FA and an accumulation of branched amino acids. Comparing HCC-F0F1 and HCC-F3F4, differential expression levels of glucose, choline derivatives and phosphoethanolamine, monounsaturated FA, triacylglycerides were identified as specific signatures. Our metabolomics analysis of HCC tissues revealed for the first time two phenotypes of HCC developed in NAFLD according to fibrosis level. This study highlighted the impact of the underlying liver disease on metabolic reprogramming of the tumor.

中文翻译：

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肝细胞癌在非酒精性脂肪肝疾病中的两种代谢组学表型，根据纤维化程度而定

非酒精性脂肪肝疾病（NAFLD）被认为是肝细胞癌（HCC）的主要病因。在非肝硬化肝组织中，NAFLD-HCC可能会在40％至50％的患者中升高。这项研究的目的是根据纤维化水平（F0F1 vs. F3F4）确定肝癌的不同代谢途径。应用了非靶向代谢组学策略。我们分析了52对人类HCC和邻近的非肿瘤组织，其中包括26例在严重纤维化或肝硬化（F3F4）中发展的HCC和26例在无或轻度纤维化（F0F1）中发展的HCC。使用¹分析组织提取物H核磁共振波谱。基于遗传算法的优化进化方法用于鉴别判别性代谢物。我们根据纤维化水平鉴定了区分NAFLD-HCC两组的34种代谢物，从而使我们能够提出NAFLD-HCC的两种代谢组学表型。我们表明，HCC-F0F1主要过表达胆碱衍生物和谷氨酰胺，而HCC-F3F4的特征是单不饱和脂肪酸（FA）含量降低，饱和FA含量增加和分支氨基酸的积累。比较HCC-F0F1和HCC-F3F4，可以确定葡萄糖，胆碱衍生物和磷酸乙醇胺，单不饱和FA，三酰基甘油酯的差异表达水平为特定特征。我们对肝癌组织的代谢组学分析首次揭示了根据纤维化水平在NAFLD中出现的两种肝癌表型。这项研究强调了潜在的肝脏疾病对肿瘤代谢重编程的影响。