Journal
BIOMEDICINE & PHARMACOTHERAPY
Volume 96, Issue -, Pages 1292-1298Publisher
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.biopha.2017.11.083
Keywords
Obeticholic acid; Liver injury; FXR; ATF4; Autophagy
Funding
- New Advanced Technology Project at the Shanghai City Hospital Development Center [SHDC12014116]
- Science and Technology Commission of Shanghai Municipality [16411970300, 17411968900]
- Shanghai Municipal Education Commission-Gaofeng Clinical Medicine Grant support [20171928]
- Shanghai Municipal Commission of Health and Family Planning [201740025]
- Shanghai Jiao Tong University School of Medicine [17XJ11018]
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Background: Cholestasis, as a main manifestation, induces liver injury during sepsis. The farnesoid X receptor (FXR) plays an important role in regulating bile acid homeostasis. Whether FXR activation by its agonist obeticholic acid (OCA) is contributed to improve sepsis-induced liver injury remains unknown. Objective: The aim of the present study was to investigate the effect of OCA on lipopolysaccharide (LPS)-induced acute liver injury in mice. Results: 8-week old male C57BL/6J mice were randomly divided into control group, LPS group, oral OCA group and LPS plus oral OCA (LPS + OCA) group. The serum and livers were collected for further analysis. Serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bile acid (TBA) and total bilirubin (TBIL) were measured at indicated time after LPS administration. Liver sections were stained with hematoxylin & eosin (H&E). Orally OCA pretreatment stimulated the expression of FXR and BSEP in livers and protected mice from LPS-induced hepatocyte apoptosis and inflammatory infiltration. Consistently, LPS-induced higher serum levels of ALT, AST, TBA and TBIL were significantly reversed by OCA administration. Meanwhile, the mRNA levels of interleukin 1 beta (IL-1 beta), tumor necrosis factor a (TNF-alpha) and IL-6 were decreased in livers of mice in LPS + OCA group compared with LPS group. Further investigation indicated that the higher expression of ATF4 and LC3II/I were associated with the protective effect of OCA on LPS-induced liver injury. Conclusion: Orally OCA pretreatment protects mice from LPS-induced liver injury possibly contributed by improved bile acid homeostasis, decreased inflammatory factors and ATF4-mediated autophagy activity in hepatocytes.
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