UGT2B28、FABP5、CYP2C9基因在脂肪酸代谢异常所致大鼠肝纤维化发生中的作用

Important roles of UGT2B28, FABP5, and CYP2C9 in the development of rat liver fibrosis induced by abnormal fatty acid metabolism

目的脂肪酸代谢异常是二甲基亚硝胺(Dimethylniyrosamine,DMN)诱导导致大鼠肝纤维化发生的重要机制之一,本研究进一步阐明DMN诱发肝纤维化发生的关键调控基因。方法通过复制经典的DMN诱导肝纤维化大鼠模型,在造模2周、4周时分别留取大鼠血清及肝脏组织。血清进行肝功能及血脂分析,肝组织进行全基因芯片分析,借助生物信息分析软件,对芯片数据进行深度挖掘。结果造模2周、造模4周模型组大鼠血清ALT分别为(45.83±5.03)U/L、(88.06±15.51)U/L高于对照组(25.28±3.03)U/L;血清AST分别为(69.17±5.20)、(108.10±17.31)U/L,高于对照组(61.44±11.82)U/L;血清TG分别为(1.11±0.30)、(0.77±0.10)mmol/L,高于对照组(0.77±0.22)mmol/L;血清FFA分别为(0.26±0.04)、(0.49±0.18)mmol/L,高于对照组(0.51±0.18)mmol/L,差异均有统计学意义(均P<0.05)。55个共享差异基因(Log Ratio>2)主要参与了肝纤维化发生的9条信号通路,主要涉及细胞增殖、脂肪酸代谢、细胞凋亡、细胞死亡等生物学功能。共享差异基因UGT2B28在2周模型组和4周模型组中明显上调大于5倍,FABP5在2周模型组中明显上调大于5倍,CYP2C9在4周模型组中明显下调大于5倍。共享差异基因UGT2B28、FABP5和CYP2C9三个基因均参与了脂代谢的所有过程。结论共享差异基因UGT2B28、FABP5和CYP2C9在脂肪酸代谢异常引起的肝纤维发生机制中具有关键作用。

Objective Purpose Abnormal fatty acid metabolism has been found to be one of the mechanisms of dimethylnitrosamine(DMN)-induced hepatic fibrosis.In this study,we further elucidated the key regulatory genes of fatty acid metabolism in DMN-induced rat model of hepatic fibrosis.Methods The classical rat model of DMN-induced liver fibrosis was replicated.Serum and liver tissues were collected at 2 and 4 weeks of modeling.The serum samples were analyzed for liver function and lipid metabolism.Whole gene microarray was performed with the liver tissues and the microarray data were deeply mined with bioinformatic analysis software.Results Serum ALT and AST levels were(25.28±3.03)U/L and(69.17±5.20)U/L,and(45.83±5.03)U/L and(108.10±17.31)U/L in the model group at 2 weeks and 4 weeks of modeling,respectively,which was significantly higher than those of(25.28±3.03)U/L and(61.44±11.82)U/L in the control group(P<0.05);Similarly,serum TG and FFA levels were(1.11±0.30)and(0.26±0.04),and(0.77±0.10)and(0.49±0.18)mmol/L in the model group at 2 weeks and 4 weeks of modeling,respectively,which was significantly higher than(0.77±0.22)and(0.51±0.18)mmol/L in the control group(P<0.01 for TG,and P<0.05 for FFA).There were 55 shared differential genes(Log Ratio>2)were identified,which were enriched in 9 signaling pathways associated with cell proliferation,fatty acid metabolism,apoptosis,cell death and other biological functions.The shared differential gene UGT2B28 was significantly up-regulated(>5-fold)in 2 weeks and 4 weeks liver samples of the model group,while FABP5 in the liver samples of the model group at 2 weeks and CYP2C9 in the liver samples of the model group at 4 weeks were significantly up-regulated(>5-fold).UGT2B28,FABP5 and CYP2C9 were involved in all processes of lipid metabolism.Conclusion The shared differential genes UGT2B28,FABP5 and CYP2C9 play key roles in the mechanism of liver fibrogenesis associated with abnormal fatty acid metabolism.