Obeticholic acid protects against carbon tetrachloride-induced acute liver injury and inflammation
| Autor: | Zhi-Hui Zhang, Yuan-Hua Chen, Hua Wang, Yan Lu, Jun-Xian Wang, Da-Gang Zhang, Li Tao, Bi-Wei Wang, Jian-Qing Wang, De-Xiang Xu, Xi Chen, Cheng Zhang |
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| Rok vydání: | 2017 |
| Předmět: |
Male
0301 basic medicine MAPK/ERK pathway medicine.drug_class p38 mitogen-activated protein kinases Receptors Cytoplasmic and Nuclear Apoptosis CCL4 Inflammation Pharmacology Chenodeoxycholic Acid Toxicology p38 Mitogen-Activated Protein Kinases digestive system Mice 03 medical and health sciences chemistry.chemical_compound parasitic diseases medicine Animals Extracellular Signal-Regulated MAP Kinases Protein kinase B Bile acid Carbon Tetrachloride Poisoning business.industry Obeticholic acid Alanine Transaminase digestive system diseases eye diseases 030104 developmental biology chemistry Immunology Hepatocytes Farnesoid X receptor Chemical and Drug Induced Liver Injury medicine.symptom business Proto-Oncogene Proteins c-akt |
| Zdroj: | Toxicology and Applied Pharmacology. 314:39-47 |
| ISSN: | 0041-008X |
| DOI: | 10.1016/j.taap.2016.11.006 |
| Popis: | 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 (0.15ml/kg). In CCl4+OCA group, mice were orally with OCA (5mg/kg) 48, 24 and 1h 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-α and Il-1β. By contrast, OCA pretreatment elevated hepatic anti-inflammatory gene Il-4. Further analysis showed that OCA pretreatment inhibited hepatic IκB phosphorylation and blocked nuclear translocation of NF-κB 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. |
| Databáze: | OpenAIRE |
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