Lin Xiangping, Liu Xinyu, Triba Mohamed N, Bouchemal Nadia, Liu Zhicheng, Walker Douglas I, Palama Tony, Le Moyec Laurence, Ziol Marianne, Helmy Nada, Vons Corinne, Xu Guowang, Prip-Buus Carina, Savarin Philippe
Sorbonne Paris Nord University, Chemistry Structures Properties of Biomaterials and Therapeutic Agents Laboratory (CSPBAT), Nanomédecine Biomarqueurs Détection Team (NBD), The National Center for Scientific Research (CNRS), UMR 7244, 74 Rue Marcel Cachin, CEDEX, 93017 Bobigny, France.
CAS Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, China.
Metabolites. 2022 Nov 8;12(11):1081. doi: 10.3390/metabo12111081.
Metabolic dysfunction-associated fatty liver disease (MAFLD) is a complex disorder that is implicated in dysregulations in multiple biological pathways, orchestrated by interactions between genetic predisposition, metabolic syndromes and environmental factors. The limited knowledge of its pathogenesis is one of the bottlenecks in the development of prognostic and therapeutic options for MAFLD. Moreover, the extent to which metabolic pathways are altered due to ongoing hepatic steatosis, inflammation and fibrosis and subsequent liver damage remains unclear. To uncover potential MAFLD pathogenesis in humans, we employed an untargeted nuclear magnetic resonance (NMR) spectroscopy- and high-resolution mass spectrometry (HRMS)-based multiplatform approach combined with a computational multiblock omics framework to characterize the plasma metabolomes and lipidomes of obese patients without ( = 19) or with liver biopsy confirmed MAFLD ( = 63). Metabolite features associated with MAFLD were identified using a metabolome-wide association study pipeline that tested for the relationships between feature responses and MAFLD. A metabolic pathway enrichment analysis revealed 16 pathways associated with MAFLD and highlighted pathway changes, including amino acid metabolism, bile acid metabolism, carnitine shuttle, fatty acid metabolism, glycerophospholipid metabolism, arachidonic acid metabolism and steroid metabolism. These results suggested that there were alterations in energy metabolism, specifically amino acid and lipid metabolism, and pointed to the pathways being implicated in alerted liver function, mitochondrial dysfunctions and immune system disorders, which have previously been linked to MAFLD in human and animal studies. Together, this study revealed specific metabolic alterations associated with MAFLD and supported the idea that MAFLD is fundamentally a metabolism-related disorder, thereby providing new perspectives for diagnostic and therapeutic strategies.
代谢功能障碍相关脂肪性肝病（MAFLD）是一种复杂的疾病，涉及多种生物途径的失调，由遗传易感性、代谢综合征和环境因素之间的相互作用所调控。对其发病机制的了解有限是MAFLD预后和治疗方案发展的瓶颈之一。此外，由于持续的肝脂肪变性、炎症和纤维化以及随后的肝损伤导致代谢途径改变的程度仍不清楚。为了揭示人类潜在的MAFLD发病机制，我们采用了一种基于非靶向核磁共振（NMR）光谱和高分辨率质谱（HRMS）的多平台方法，并结合计算多组学框架来表征无肝活检证实的MAFLD（n = 19）或有肝活检证实的MAFLD（n = 63）的肥胖患者的血浆代谢组和脂质组。使用代谢组全关联研究流程识别与MAFLD相关的代谢物特征，该流程测试了特征反应与MAFLD之间的关系。代谢途径富集分析揭示了16条与MAFLD相关的途径，并突出了途径变化，包括氨基酸代谢、胆汁酸代谢、肉碱穿梭、脂肪酸代谢、甘油磷脂代谢、花生四烯酸代谢和类固醇代谢。这些结果表明能量代谢存在改变，特别是氨基酸和脂质代谢，并指出这些途径与肝功能改变、线粒体功能障碍和免疫系统紊乱有关，这些在之前的人类和动物研究中已与MAFLD相关联。总之，本研究揭示了与MAFLD相关的特定代谢改变，并支持MAFLD从根本上是一种与代谢相关的疾病这一观点，从而为诊断和治疗策略提供了新的视角。
