Obeticholic acid protects against carbon tetrachloride-induced acute liver injury and inflammation
Obeticholic acid protects against carbon tetrachloride-induced acute liver injury and inflammation
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奥贝胆酸可预防四氯化碳引起的急性肝损伤和炎症
DOI：
10.1016/j.taap.2016.11.006
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发表时间：
2017-01-01
影响因子：
3.8
通讯作者：
Xu, De-Xiang
中科院分区：
文献类型：
--
作者：
Zhang, Da-Gang;Zhang, Cheng;Xu, De-Xiang
法尼醇X受体（FXR）是一种配体激活的转录因子，在调节胆汁酸稳态中起重要作用。本研究的目的是探讨奥贝胆酸（OCA），一种新的合成FXR激动剂，四氯化碳（CCl 4）诱导的急性肝损伤的影响。小鼠腹腔注射CCl 4（0.15 ml/kg）。在CCl 4 + OCA组中，小鼠在CCl 4前48、24和1 h经口给予OCA（5 mg/kg）。正如预期的那样，肝脏FXR被OCA激活。有趣的是，OCA预处理减轻CCl 4诱导的血清ALT升高和肝坏死。此外，OCA预处理抑制四氯化碳诱导的肝细胞凋亡。进一步的实验表明，OCA抑制CCl 4诱导的肝趋化因子基因Mcp-1、Mip-2和Kc。此外，OCA抑制CCl 4诱导的肝脏促炎基因TNF-α和IL-1 β。相比之下，OCA预处理升高肝脏抗炎基因IL-4。进一步分析表明，OCA预处理抑制肝I κ B磷酸化，并阻断CCl 4诱导的急性肝损伤过程中NF-κ B p65和p50亚基的核转位。此外，OCA预处理抑制CCl 4诱导的急性肝损伤中的肝Akt、ERK和p38磷酸化。这些结果表明，OCA可预防CCl 4诱导的急性肝损伤和炎症。合成FXR激动剂可能是急性肝损伤期间肝脏炎症的有效解毒剂。(C)版权所有© 2016 Elsevier Inc.
The farnesoid X receptor (FXR) is a ligand-activated transcription factor that plays important roles in regulating bile acid homeostasis. The aim of the present study was to investigate the effects of obeticholic acid (OCA), a novel synthetic FXR agonist, carbon tetrachloride (CCl4)-induced acute liver injury. Mice were intraperitoneally injected with CCl4 (0.15 ml/kg). In CCl4 + OCA group, mice were orally with OCA (5 mg/kg) 48, 24 and 1 h before CCl4. As expected, hepatic FXR was activated by OCA. Interestingly, OCA pretreatment alleviated CCl4-induced elevation of serum ALT and hepatic necrosis. Moreover, OCA pretreatment inhibited CCl4-induced hepatocyte apoptosis. Additional experiment showed that OCA inhibits CCl4-induced hepatic chemokine gene Mcp-1, Mip-2 and Kc. Moreover, OCA inhibits CCl4-induced hepatic pro-inflammatory gene Tnf-alpha and Il-1 beta. By contrast, OCA pretreatment elevated hepatic anti-inflammatory gene Il-4. Further analysis showed that OCA pretreatment inhibited hepatic I kappa B phosphorylation and blocked nuclear translocation of NF-kappa B p65 and p50 subunits during CCl4-induced acute liver injury. In addition, OCA pretreatment inhibited hepatic Akt, ERK and p38 phosphorylation in CCl4-induced acute liver injury. These results suggest that OCA protects against CCl4-induced acute liver injury and inflammation. Synthetic FXR agonists may be effective antidotes for hepatic inflammation during acute liver injury. (C) 2016 Elsevier Inc All rights reserved.