Hepatic triglyceride content is intricately associated with numerous metabolites and biochemical pathways

Background and Aims 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. Methods 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. Results Our analyses revealed that 118 metabolites were univariately associated with HTGC ( p ‐value <6.59 × 10 −5 ), 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/ . Conclusions 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.