Objective: To study the effects of simvastatin on lipid metabolism of liver samples in mice by metabolomics. Methods: The metabolite fingerprint information of liver samples of mice treated with simvastatin was collected by ultra-performance liquid chromatography-high resolution time-of-flight mass spectrometry (UPLC-Q TOF MS) using Acquity BEH C18 column, water-acetonitrile gradient eluted mobile phase, flow rate was 0.5 mL·min-1, column temperature was 35 ℃.The injection chamber temperature was 4 ℃, and the injection volume was 10 μL. The conditions of mass spectrometer were ectrospray ion source, positive ion detection mode, scanning range m/z 100-1 000, capillary voltage 3.1 kV and cone-hole voltage of 30 V,100 pg·mL-1 leucine enkephalin (LE) solution as quality correction solution. Metabolic profile analysis was performed by data acquisition. The peak information in the total ion flow chromatogram was read. The acquired data was processed by using principal component analysis. After screening for candidate differential metabolites, the structure of the differential metabolites was identified by comparing the primary and secondary mass spectrometry fragment information with the database. The effect of simvastatin on lipid synthesis was verified by Western blot and isotope radio metabolic flow analysis. Results: After administration of simvastatin, eight metabolic differentials were found in liver tissues. The content of lysophospholipids increased in each dose group, with LysoPE (18∶1) being 1.14, 1.24, and 1.31 times compared to the control group in the low, medium and high dose groups, respectively. LysoPC (16∶0) was 1.58, 2.05, and 2.32 times compared to the control group in the low, medium and high dose groups, respectively. The contents of fatty acids and phospholipids, such as arachidonic acid, petroselinic acid, O-arachidonoylglycidol, 17(S)-HETE, PC(16∶0/O-1∶0), DG(16∶1/17∶1/0∶0) were reduced and showed a dose correlation. The largest decrease was observed in PC (16∶0/O-1∶0), which was 0.68, 0.43 and 0.38 times of the control group in the low, medium and high dose groups, respectively. Through isotope tracing, the effect of simvastatin on lipid synthesis was verified and showed a dose correlation, and regulated the rate-limi ting enzyme of lipid synthesis. It was confirmed that the administration of simvastatin inhibited the synthesis of hepatic lipids, which ultimately led to a decrease in total lipid. Conclusion: The results suggest that modulation of hepatic lipid metabolism is one of the ways in which simvastatin achieve its lipid-lowering effects.
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