Rifampicin-induced injury in HepG2 cells is alleviated by TUDCA via increasing bile acid transporters expression and enhancing the Nrf2-mediated adaptive response.
Rifampicin-induced injury in HepG2 cells is alleviated by TUDCA via increasing bile acid transporters expression and enhancing the Nrf2-mediated adaptive response.
复制标题
TUDCA 通过增加胆汁酸转运蛋白的表达和增强 Nrf2 介导的适应性反应来减轻利福平诱导的 HepG2 细胞损伤。
DOI：
10.1016/j.freeradbiomed.2017.07.003
复制
发表时间：
2017-11
影响因子：
7.4
通讯作者：
Yuxian Shen
中科院分区：
文献类型：
--
作者：
Weiping Zhang;Lihong Chen;Hui Feng;Wei Wang;Yi Cai;Fen Qi;Xiaofang Tao;Jun Liu;Yujun Shen;Xiaofei Ren;Xi Chen;Jianming Xu;Yuxian Shen
胆汁酸转运蛋白和核因子红细胞2相关因子（Nrf-2）介导的适应性反应在药物性肝损伤（DILI）的发生中起重要作用。然而，很少有人知道的利福平（RFP）诱导的细胞损伤的适应性反应的贡献。本研究发现RFP可降低HepG 2细胞的存活率，并升高细胞内乳酸脱氢酶（LDH）、丙氨酸氨基转移酶（ALT）、天冬氨酸氨基转移酶（AST）、碱性磷酸酶（AKP）、γ-谷氨酰转移酶（γ-GT）、总胆红素（TBIL）、直接胆红素（DBIL）、间接胆红素（IBIL）、总胆汁酸（TBA）和三磷酸腺苷（ATP）在细胞培养上清液中的浓度和时间依赖性的方式。RFP可增加胆汁酸转运蛋白和mRNA的表达，如胆汁盐输出泵（BSEP）、多药耐药蛋白1（MDR 1）、多药耐药相关蛋白2（MRP 2）、Na+/牛磺胆酸盐协同转运蛋白（NTCP）、有机阴离子转运蛋白2（OATP 2）、有机溶质转运蛋白β（OSTβ）和Nrf 2。瞬时敲除Nrf 2后，RFP处理后BSEP、MDR 1、MRP 2、NTCP、OATP 2和OSTβ蛋白及mRNA表达水平均不同程度降低。此外，细胞存活率降低，而细胞培养上清液中的LDH水平升高。Nrf 2基因的过表达产生相反的效果。牛磺熊去氧胆酸（TUDCA）处理增加了胆汁酸转运蛋白和Nrf 2的表达水平，降低了葡萄糖调节蛋白78（GRP 78）、PKR样ER激酶（PERK）、转录激活因子4（ATF 4）和C/EBP同源蛋白（CHOP）的表达水平，并抑制了RFP诱导的氧化应激。TUDCA还能减少细胞凋亡，提高细胞存活率，降低细胞培养上清中LDH、ALT、AST、AKP、γ-GT、TBIL、DBIL、IBIL、TBA和ATP的水平。因此，TUDCA通过增强胆汁酸转运蛋白的表达和Nrf 2介导的适应性反应来减轻RFP诱导的HepG 2细胞损伤。
Bile acid transporters and the nuclear factor erythroid 2-related factor (Nrf-2)-mediated adaptive response play important roles in the development of drug-induced liver injury (DILI). However, little is known about the contribution of the adaptive response to rifampicin (RFP)-induced cell injury. In this study, we found RFP decreased the survival rate of HepG2 cells and increased the levels of lactate dehydrogenase (LDH), alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (AKP), γ-glutamyl-transferase (γ-GT), total bilirubin (TBIL), direct bilirubin (DBIL), indirect bilirubin (IBIL), total bile acid (TBA) and adenosine triphosphate (ATP) in the cell culture supernatants in both a concentration- and a time-dependent manner. RFP increased the expression levels of bile acid transporter proteins and mRNAs, such as bile salt export pump (BSEP), multidrug resistance protein 1 (MDR1), multidrug resistance-associated protein 2 (MRP2), Na+/taurocholate cotransporter (NTCP), organic anion transporting protein 2 (OATP2), organic solute transporter β (OSTβ) and Nrf2. Following the transient knockdown of Nrf2 and treatment with RFP, the expression levels of the BSEP, MDR1, MRP2, NTCP, OATP2 and OSTβ proteins and mRNAs were decreased to different degrees. Moreover, the cell survival was decreased, whereas the LDH level in the cell culture supernatant was increased. Overexpression of the Nrf2 gene produced the opposite effects. Treatment with tauroursodeoxycholic acid (TUDCA) increased the expression levels of the bile acid transporters and Nrf2, decreased the expression levels of glucose-regulated protein 78 (GRP78), PKR-like ER kinase (PERK), activating transcription factor 4 (ATF4), and C/EBP-homologous protein (CHOP), and inhibited RFP-induced oxidative stress. Moreover, TUDCA reduced cell apoptosis, increased cell survival and decreased the levels of LDH, ALT, AST, AKP, γ-GT, TBIL, DBIL, IBIL, TBA and ATP in the cell culture supernatant. Therefore, TUDCA alleviates RFP-induced injury in HepG2 cells by enhancing bile acid transporters expression and the Nrf2-mediated adaptive response.
登录
查看更多内容
影响因子：
4.3
作者：
Gonzalez FJ;Fang ZZ;Ma X
通讯作者：
Ma X
DOI：
10.1159/000507171
发表时间：
2020
期刊：
Fast Facts: Glioblastoma
影响因子：
--
作者：
P. Croskerry
通讯作者：
P. Croskerry
DOI：
--
发表时间：
2011-11
期刊：
Tropical gastroenterology : official journal of the Digestive Diseases Foundation
影响因子：
--
作者：
H. Devarbhavi
通讯作者：
H. Devarbhavi
DOI：
10.1016/s0140-6736(87)92679-1
发表时间：
1987-12
期刊：
The Lancet
影响因子：
--
作者：
Dr. Ron Short
通讯作者：
Dr. Ron Short
DOI：
10.1055/s-2008-1075823
发表时间：
2008-05
期刊：
Semin Hear
影响因子：
--
作者：
Ph.D Sandra Abbott Gabbard;Au. Jennifer Schryer;Ph.D R.S. Ackley
通讯作者：
Ph.D Sandra Abbott Gabbard;Au. Jennifer Schryer;Ph.D R.S. Ackley