Due to the complex pathogenesis, the molecular mechanism of non-alcoholic steatohepatitis (NASH) remains unclear. In this study, we aimed to reveal the comprehensive metabolic and signaling pathways in the occurrence of NASH.
C57BL/6 mice were treated with high-fat diet for four months to mimic the NASH phenotype. After the treatment, the physiochemical parameters were evaluated, and the liver tissues were prepared for untargeted metabolomic analysis with ultra-performance liquid chromatography coupled with Q-TOF mass spectrometry (UPLC-Q-TOF-MS). Then, three relevant Gene Expression Omnibus (GEO) datasets were selected for integrative analysis of differentiated mRNA and metabolites.
The levels of PE (16:1(9Z)/20:4(5Z,8Z,11Z,14Z)), Oleic acid,and SM(d18:0/12:0) were significantly increased, and the content of adenosine was severely reduced in NASH mice. The integrated interpretation of transcriptomic and metabolomic data indicated that the glycerophospholipid metabolism and necroptosis signaling were evidently affected in the development of NASH. The high level of SM(d18:0/12:0) may be related to the expression of aSmase, and the elevated arachidonic acid was coordinated with the upregulation of cPLA2 in the necroptosis pathway.
In summary, the inflammatory response, necroptosis, and glycerophospholipid may severe as potential targets for mechanistic exploration and clinical practice in the treatment of NASH.

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