Chen Y H, Zhan Z, Hu P, Ren H, Peng M L
Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing 400010, China.
Zhonghua Gan Zang Bing Za Zhi. 2019 Jul 20;27(7):533-540. doi: 10.3760/cma.j.issn.1007-3418.2019.07.011.
To analyze non-alcoholic steatohepatitis (NASH)-related differentially expressed genes (DEGs) by bioinformatics methods to find key pathways and potential therapeutic targets for NASH. GSE61260 chip was downloaded from the public microarray database and liver biopsy samples from 24 NASH cases and 38 healthy controls were included. The Limma software package in R language was used to screen DEGs under the condition of difference multiple > 1.5 and adj. < 0.05. The clusterProfiler software package was used for GO analysis and KEGG analysis. The STRING online database was used for protein-protein interaction analysis, and the L1000 and DrugBank databases were used for drug prediction. Compared with healthy control group, 857 DEGs were screened out in NASH group including 167 up-regulated genes and 690 down-regulated genes. GO analysis showed that DEGs were mainly involved in inflammation and cholesterol metabolism. KEGG analysis showed that DEGs were mainly enriched in PPAR, non-alcoholic fatty liver disease, oxidative phosphorylation and other signaling pathways. Among them, eight genes of ACSL4, CYP7A1, FABP4, FABP5, lipoprotein lipase, ME1, OLR1 and PLIN1 were enriched in PPAR signaling pathway, and 165 interaction nodes were formed with 47 DEGs-encoded proteins. Lipoprotein lipase interacted with 21 DEGs, and its up-regulated expression had improved lipid metabolism, insulin resistance and anti-inflammatory effects. Four drugs (gemfibrozil, bezafibrate, omega-3 carboxylic acid and glycyrrhizic acid) were screened by L1000 and DrugBank to activate lipoprotein lipase. Presently, these four drugs are clinically used to treat hypertriglyceridemia or to improve inflammation. In this regard, we speculated that the pharmacological effects of these four drugs had improved NASH by activating lipoprotein lipase to promote liver lipid metabolism and alleviate inflammation. PPAR signaling pathway is closely associated to the occurrence and development of NASH, and thereby lipoprotein lipase agonist is a new attempt to treat NASH.
通过生物信息学方法分析非酒精性脂肪性肝炎（NASH）相关的差异表达基因（DEGs），以寻找NASH的关键通路和潜在治疗靶点。从公共微阵列数据库下载GSE61260芯片，并纳入24例NASH病例和38例健康对照的肝活检样本。使用R语言中的Limma软件包在差异倍数>1.5和校正P值<0.05的条件下筛选DEGs。使用clusterProfiler软件包进行基因本体（GO）分析和京都基因与基因组百科全书（KEGG）分析。使用STRING在线数据库进行蛋白质-蛋白质相互作用分析，并使用L1000和DrugBank数据库进行药物预测。与健康对照组相比，NASH组筛选出857个DEGs，其中上调基因167个，下调基因690个。GO分析表明，DEGs主要参与炎症和胆固醇代谢。KEGG分析表明，DEGs主要富集于过氧化物酶体增殖物激活受体（PPAR）、非酒精性脂肪性肝病、氧化磷酸化等信号通路。其中，ACSL4、CYP7A1、FABP4、FABP5、脂蛋白脂肪酶、苹果酸酶1、氧化低密度脂蛋白受体1（OLR1）和脂滴包被蛋白1（PLIN1）这8个基因在PPAR信号通路中富集，并与47个DEGs编码的蛋白质形成165个相互作用节点。脂蛋白脂肪酶与21个DEGs相互作用，其上调表达具有改善脂质代谢、胰岛素抵抗和抗炎作用。通过L1000和DrugBank筛选出4种药物（吉非贝齐、苯扎贝特、ω-3羧酸和甘草酸）来激活脂蛋白脂肪酶。目前，这4种药物在临床上用于治疗高甘油三酯血症或改善炎症。在这方面，我们推测这4种药物的药理作用通过激活脂蛋白脂肪酶促进肝脏脂质代谢和减轻炎症来改善NASH。PPAR信号通路与NASH的发生发展密切相关，因此脂蛋白脂肪酶激动剂是治疗NASH的一种新尝试。
