title: Obeticholic acid protects against carbon tetrachloride-induced acute liver injury and inflammation.
abstract: 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.
authors.affiliation: First Affiliated Hospital, Anhui Medical University, Hefei 230022, China.
authors.forename: Da-Gang
authors.initials: DG
authors.lastname: Zhang
authors.affiliation: Department of Toxicology, Anhui Medical University, Hefei 230032, China.
authors.forename: Cheng
authors.initials: C
authors.lastname: Zhang
authors.affiliation: First Affiliated Hospital, Anhui Medical University, Hefei 230022, China.
authors.forename: Jun-Xian
authors.initials: JX
authors.lastname: Wang
authors.affiliation: Department of Toxicology, Anhui Medical University, Hefei 230032, China.
authors.forename: Bi-Wei
authors.initials: BW
authors.lastname: Wang
authors.affiliation: Department of Toxicology, Anhui Medical University, Hefei 230032, China.
authors.forename: Hua
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Toxicology, Anhui Medical University, Hefei 230032, China.
authors.forename: Zhi-Hui
authors.initials: ZH
authors.lastname: Zhang
authors.affiliation: Department of Toxicology, Anhui Medical University, Hefei 230032, China.
authors.forename: Yuan-Hua
authors.initials: YH
authors.lastname: Chen
authors.affiliation: Second Affiliated Hospital, Anhui Medical University, Hefei 230601, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Lu
authors.affiliation: Second Affiliated Hospital, Anhui Medical University, Hefei 230601, China.
authors.forename: Li
authors.initials: L
authors.lastname: Tao
authors.affiliation: Second Affiliated Hospital, Anhui Medical University, Hefei 230601, China.
authors.forename: Jian-Qing
authors.initials: JQ
authors.lastname: Wang
authors.affiliation: First Affiliated Hospital, Anhui Medical University, Hefei 230022, China.
authors.forename: Xi
authors.initials: X
authors.lastname: Chen
authors.affiliation: Department of Toxicology, Anhui Medical University, Hefei 230032, China. Electronic address: xudex@126.com.
authors.forename: De-Xiang
authors.initials: DX
authors.lastname: Xu
mesh_terms: D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002252:Carbon Tetrachloride Poisoning / Q000150:complications / Q000517:prevention & control*; D056486:Chemical and Drug Induced Liver Injury / Q000150:complications / Q000517:prevention & control*; D002635:Chenodeoxycholic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D022781:Hepatocytes / Q000737:chemistry / Q000187:drug effects; D007249:Inflammation / Q000209:etiology*; D008297:Male; D051379:Mice; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D000410:Alanine Transaminase; D002635:Chenodeoxycholic Acid; D048049:Extracellular Signal-Regulated MAP Kinases; D051057:Proto-Oncogene Proteins c-akt; D018160:Receptors, Cytoplasmic and Nuclear; D048051:p38 Mitogen-Activated Protein Kinases; D000099150:Receptor, Farnesoid X-Activated; C464660:obeticholic acid
keywords: Acute liver injury; Carbon tetrachloride (CCl(4)); Farnesoid X receptor (FXR); Inflammation; Obeticholic acid