摘要：SummaryNonalcoholic 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, andHSD17B13). The study demonstrates dysregulated liver metabolic pathways which may contribute to the progression of NAFLD.Graphical abstractDisplay OmittedHighlights•Nonalcoholic fatty liver disease is associated with metabolic disturbances•Metabolic pathways of vitamins (A, E) and glycosphingolipids are altered in NAFLD•Glycosphingolipids might be linked with complex glycosaminoglycans in fibrosis•There are metabolic differences among three common NAFLD-associated gene variantsHealth sciences; Systems biology; Omics; Metabolomics.
