Integrative analysis of hepatic metabolomic and transcriptomic data reveals potential mechanism of nonalcoholic steatohepatitis in high‐fat diet–fed mice

Abstract Background Due to the complex pathogenesis, the molecular mechanism of nonalcoholic steatohepatitis (NASH) remains unclear. In this study, we aimed to reveal the comprehensive metabolic and signaling pathways in the occurrence of NASH. Methods C57BL/6 mice were treated with high‐fat diet for 4 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 ultraperformance liquid chromatography coupled with quadrupole time‐of‐flight mass spectrometry. Then, three relevant Gene Expression Omnibus (GEO) datasets were selected for integrative analysis of differentiated messenger RNA and metabolites. Results The levels of phosphatidylethanolamine (PE) (16:1(9Z)/20:4(5Z,8Z,11Z,14Z)), oleic acid, and sphingomyelin (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 acid sphingomyelinase (ASMase), and the elevated arachidonic acid was coordinated with the upregulation of cytosol phospholipase A2 (cPLA2) in the necroptosis pathway. Conclusions In summary, the inflammatory response, necroptosis, and glycerophospholipid may serve as potential targets for mechanistic exploration and clinical practice in the treatment of NASH.