OBJECTIVE：To investigate the effects of gypenosides （GPs）on gene expression of major urinary proteins （Mups） in liver tissue of hypercholesterolemia model mice. METHODS ：C57BL/6J mice were divided into control （ND）group，model （HFD）group and GPs therapy （GP）group according to body weight （BW），with 11 mice in each group. Except for ND group ， other groups were given high-lipid diet to induce hypercholesterolemia model. From the 17th week of feeding ，ND group and HFD group were given constant volume of 0.1％CMC-Na solution intragastrically ；GP group were given GPs suspension （250 mg/kg） intragastrically，once a day ，for consecutive 22 weeks. BW ，the levels of blood glucose （BG）and blood lipid （TC，LDL-C）were detected in each group. Total RNA of liver tissue was extracted ，and reverse transcription library was constructed and RNA-seq sequencing was performed. The differentially expressed genes were screened by PCA ，volcano map and scatter plot. RT-qPCR was used for verification for differentially expressed genes. The correlation between the expression of differentially expressed genes and the above pharmacodynamic indexes was analyzed by bivariate analysis. RESULTS ：Compared with ND group ，BW，the levels of BG，TC and LDL-C in HFD group were increased significantly （P＜0.05）. Compared with HFD group ，above indexes of GP group were decreased significantly except for BW （P＜0.05）. PCA showed that the data of ND group and HFD group distributed in different quadrants ，and the data distribution of GP group was between above two groups. mRNA of Mup4，Mup5，Mup11，Mup15 and Mup21 in liver tissue of mice were increased significantly after treated with high-fat diet （P＜0.05）. mRNA of Mup3，Mup4， Mup5，Mup8，Mup12 and Mup21 were decreased significantly after treated with GPs （P＜0.05）. In ND group vs. HFD group and HFD group vs. GP group ，mRNA of Mup4，Mup5 and Mup21 genes changed significantly and the trend was opposite. Results of RT-qPCR verification showed that compared with ND group ，relative mRNA expression of Mup4，Mup5 and Mup21 gene were increased significantly in HFD group （P＜0.05）. Correlation analysis revealed that mRNA expression of Mup5 was positively correlated with the levels of TC and BG （r＝0.727 1，0.670 6，P＜0.05），mRNA expression of Mup4 and Mup21 were positively correlated with the level of BG （r＝0.737 8，0.721 5，P＜0.05）. CONCLUSIONS ：GPs can regulate the expression of Mups genes in liver tissue of hypercholesterolemia model mice ， and reduce glucose and lipid level through regulating the mRNA over-expression of Mup4，Mup5 and Mup21.