Journal
TOXICOLOGY AND APPLIED PHARMACOLOGY
Volume 314, Issue -, Pages 39-47Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.taap.2016.11.006
Keywords
Obeticholic acid; Farnesoid X receptor (FXR); Carbon tetrachloride (CCl4); Acute liver injury; Inflammation
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Funding
- National Natural Science Foundation of China [81373495, 81573512, 81400643]
- Research Fund for Backup Candidate of Academic Technology Leaders of Anhui Province [2014H027]
- Research Fund for the Doctoral Program of Higher Education of China [20133420110005]
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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.
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