Obeticholic acid protects against carbon tetrachloride-induced acute liver injury and inflammation

Journal Article · Sat Dec 31 23:00:00 EST 2016 · Toxicology and Applied Pharmacology

DOI:https://doi.org/10.1016/J.TAAP.2016.11.006· OSTI ID:22690889

Zhang, Da-Gang ^[1]; Zhang, Cheng ^[2]; Wang, Jun-Xian ^[1]; Wang, Bi-Wei; Wang, Hua; Zhang, Zhi-Hui; Chen, Yuan-Hua ^[2]; Lu, Yan; Tao, Li; Wang, Jian-Qing ^[3]; Chen, Xi ^[1]; Xu, De-Xiang ^[2]

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1. First Affiliated Hospital, Anhui Medical University, Hefei 230022 (China)
2. Department of Toxicology, Anhui Medical University, Hefei 230032 (China)
3. Second Affiliated Hospital, Anhui Medical University, Hefei 230601 (China)

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 (CCl{sub 4})-induced acute liver injury. Mice were intraperitoneally injected with CCl{sub 4} (0.15 ml/kg). In CCl{sub 4} + OCA group, mice were orally with OCA (5 mg/kg) 48, 24 and 1 h before CCl{sub 4}. As expected, hepatic FXR was activated by OCA. Interestingly, OCA pretreatment alleviated CCl{sub 4}-induced elevation of serum ALT and hepatic necrosis. Moreover, OCA pretreatment inhibited CCl{sub 4}-induced hepatocyte apoptosis. Additional experiment showed that OCA inhibits CCl{sub 4}-induced hepatic chemokine gene Mcp-1, Mip-2 and Kc. Moreover, OCA inhibits CCl{sub 4}-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 CCl{sub 4}-induced acute liver injury. In addition, OCA pretreatment inhibited hepatic Akt, ERK and p38 phosphorylation in CCl{sub 4}-induced acute liver injury. These results suggest that OCA protects against CCl{sub 4}-induced acute liver injury and inflammation. Synthetic FXR agonists may be effective antidotes for hepatic inflammation during acute liver injury. - Highlights: • OCA pretreatment activates hepatic FXR. • FXR activation protects against CCl{sub 4}-induced acute liver injury. • FXR activation inhibits hepatocyte apoptosis during CCl{sub 4}-induced liver injury. • FXR activation differentially regulates hepatic inflammatory genes. • Synthetic FXR agonists are effective antidotes for acute liver injury.

• OSTI ID: 22690889
• Journal Information: Toxicology and Applied Pharmacology, Journal Name: Toxicology and Applied Pharmacology Vol. 314; ISSN TXAPA9; ISSN 0041-008X
• Country of Publication: United States
• Language: English

Related Subjects

60 APPLIED LIFE SCIENCES
APOPTOSIS
BILE
BILE ACIDS
CARBON
CARBON TETRACHLORIDE
GENES
HOMEOSTASIS
INFLAMMATION
INJURIES
LABELLING
LIGANDS
LIVER
LIVER CELLS
LYMPHOKINES
MACROPHAGES
MICE
MONOCYTES
NECROSIS
NEOPLASMS
PHOSPHORYLATION
PHOSPHOTRANSFERASES
RECEPTORS
TRANSCRIPTION
TRANSCRIPTION FACTORS
TRANSLOCATION