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Suppression of oxidative stress and improvement of liver functions in mice by ursolic acid via LKB 1‐ AMP ‐activated protein kinase signaling
Author(s) -
Yang Yongbin,
Zhao Zhanxue,
Liu Yuanjun,
Kang Xianjiang,
Zhang Haisong,
Meng Ming
Publication year - 2015
Publication title -
journal of gastroenterology and hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.214
H-Index - 130
eISSN - 1440-1746
pISSN - 0815-9319
DOI - 10.1111/jgh.12723
Subject(s) - oxidative stress , ursolic acid , oxidative phosphorylation , protein kinase a , medicine , microbiology and biotechnology , biochemistry , kinase , endocrinology , biology , botany
Background and Aim Hepatic cirrhosis is the final stage of liver dysfunction, characterized by diffuse fibrosis, which is the main response to the liver injury. This study is to investigate the effects of ursolic acid ( UA ) on liver functions and fibrosis in bile duct ligation ( BDL ) mice and to determine the underlying mechanisms. Methods Cultured hepatocytes were treated with lipopolysaccharide ( LPS ) in the presence or absence of UA . The reactive oxygen species ( ROS ) level, protein levels of IκBα , iNOS and C ox‐2, and NF ‐ κB activation were detected, respectively. C 57/ BL 6 and AMP‐activated protein kinase ( AMPK )α2 –/– mice were subjected to BDL for 14 days. UA was administered by gavage. The markers of liver function and oxidative stress, and liver histopathology were analyzed after treatment. Results Treatment of hepatocytes with UA dose‐dependently activates AMPK , which is abolished by silence of liver kinase B 1 ( LKB 1). LPS significantly increased ROS productions, apoptosis, NF ‐ κB activation, and expressions of iNOS and C ox‐2 in cultured hepatocytes. All these effects were blocked by co‐incubation with UA . Importantly, silence of LKB 1, AMPK , or iNOS / C ox‐2 by small interference RNA transfection reversed UA ‐induced effects in cultured cells. In an animal study, 14‐day BDL induced liver fibrosis and liver injury, accompanied with increased oxidative stress and protein expressions of iNOS and C ox‐2 in liver. Treatment of UA significantly attenuated the BDL ‐induced detrimental effects in wild‐type mice but not in AMPK α2 –/– mice. Conclusion UA via LKB 1‐ AMPK signaling offers protective effects on BDL ‐induced liver injury in mice, which may be related to inhibition of oxidative stress.