Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, the Netherlands.
Department of Human Genetics, Leiden University Medical Center, Leiden, the Netherlands.
Liver Int. 2023 Jul;43(7):1458-1472. doi: 10.1111/liv.15575. Epub 2023 Apr 5.
Non-alcoholic fatty liver disease (NAFLD) is characterized by the pathological accumulation of triglycerides in hepatocytes and is associated with insulin resistance, atherogenic dyslipidaemia and cardiometabolic diseases. Thus far, the extent of metabolic dysregulation associated with hepatic triglyceride accumulation has not been fully addressed. In this study, we aimed to identify metabolites associated with hepatic triglyceride content (HTGC) and map these associations using network analysis.
To gain insight in the spectrum of metabolites associated with hepatic triglyceride accumulation, we performed a comprehensive plasma metabolomics screening of 1363 metabolites in apparently healthy middle aged (age 45-65) individuals (N = 496) in whom HTGC was measured by proton magnetic resonance spectroscopy. An atlas of metabolite-HTGC associations, based on univariate results, was created using correlation-based Gaussian graphical model (GGM) and genome scale metabolic model network analyses. Pathways associated with the clinical prognosis marker fibrosis 4 (FIB-4) index were tested using a closed global test.
Our analyses revealed that 118 metabolites were univariately associated with HTGC (p-value <6.59 × 10 ), including 106 endogenous, 1 xenobiotic and 11 partially characterized/uncharacterized metabolites. These associations were mapped to several biological pathways including branched amino acids (BCAA), diglycerols, sphingomyelin, glucosyl-ceramide and lactosyl-ceramide. We also identified a novel possible HTGC-related pathway connecting glutamate, metabolonic lactone sulphate and X-15245 using the GGM network. These pathways were confirmed to be associated with the FIB-4 index as well. The full interactive metabolite-HTGC atlas is provided online: https://tofaquih.github.io/AtlasLiver/.
The combined network and pathway analyses indicated extensive associations between BCAA and the lipids pathways with HTGC and the FIB-4 index. Moreover, we report a novel pathway glutamate-metabolonic lactone sulphate-X-15245 with a potential strong association with HTGC. These findings can aid elucidating HTGC metabolomic profiles and provide insight into novel drug targets for fibrosis-related outcomes.
非酒精性脂肪性肝病（NAFLD）的特征是肝细胞内甘油三酯的病理性积累，与胰岛素抵抗、动脉粥样硬化性血脂异常和心脏代谢疾病有关。迄今为止，与肝甘油三酯（HTGC）积累相关的代谢失调程度尚未得到充分阐明。在这项研究中，我们旨在确定与肝甘油三酯含量（HTGC）相关的代谢物，并使用网络分析来绘制这些关联。
为了深入了解与肝内甘油三酯堆积相关的代谢物谱，我们对 496 名年龄在 45-65 岁之间的健康中年人（年龄 45-65 岁）进行了全面的血浆代谢组学筛选，通过质子磁共振波谱测量 HTGC。基于单变量结果，使用基于相关的高斯图形模型（GGM）和全基因组代谢模型网络分析创建了代谢物-HTGC 关联图谱。使用封闭全局检验测试与纤维化 4 （FIB-4）指数临床预后标志物相关的途径。
我们的分析显示，有 118 种代谢物与 HTGC 呈单变量相关（p 值<6.59×10），包括 106 种内源性、1 种外源性和 11 种部分特征/非特征代谢物。这些关联映射到几个生物途径，包括支链氨基酸（BCAA）、二甘油、神经鞘磷脂、葡糖基神经酰胺和乳酰神经酰胺。我们还使用 GGM 网络鉴定了一个连接谷氨酸、代谢性乳酮硫酸盐和 X-15245 的新的可能与 HTGC 相关的途径。这些途径也被证实与 FIB-4 指数相关。完整的交互式代谢物-HTGC 图谱可在网上获得：https://tofaquih.github.io/AtlasLiver/。
联合网络和途径分析表明，BCAA 和脂质途径与 HTGC 和 FIB-4 指数之间存在广泛的关联。此外，我们报告了一个新的途径谷氨酸-代谢性乳酮硫酸盐-X-15245，与 HTGC 有潜在的强关联。这些发现可以帮助阐明 HTGC 的代谢组学特征，并为纤维化相关结果的新型药物靶点提供见解。
