Suppression of oxidative stress and improvement of liver functions in mice by ursolic acid via LKB1-AMP-activated protein kinase signaling.

Abstract

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 Cox-2, and NF-κB activation were detected, respectively. C57/BL6 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 B1 (LKB1). LPS significantly increased ROS productions, apoptosis, NF-κB activation, and expressions of iNOS and Cox-2 in cultured hepatocytes. All these effects were blocked by co-incubation with UA. Importantly, silence of LKB1, AMPK, or iNOS/Cox-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 Cox-2 in liver. Treatment of UA significantly attenuated the BDL-induced detrimental effects in wild-type mice but not in AMPKα2(-/-) mice.

CONCLUSION:

UA via LKB1-AMPK signaling offers protective effects on BDL-induced liver injury in mice, which may be related to inhibition of oxidative stress.

• Authors: Yongbin Yang, Zhanxue Zhao, Yuanjun Liu, Xianjiang Kang, Haisong Zhang, Ming Meng
• Journal: Journal of gastroenterology and hepatology (J Gastroenterol Hepatol) Vol. 30 Issue 3 Pg. 609-18 (Mar 2015) ISSN: 1440-1746 [Electronic] Australia
• PMID: 25168399 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2014 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd.

Chemical References

• Lipopolysaccharides
• Reactive Oxygen Species
• Triterpenes
• Nitric Oxide Synthase Type II
• Nos2 protein, mouse
• Ptgs2 protein, mouse
• Cyclooxygenase 2
• Protein Serine-Threonine Kinases
• Stk11 protein, mouse
• AMP-Activated Protein Kinases

Topics

• AMP-Activated Protein Kinases (physiology)
• Animals
• Cells, Cultured
• Cyclooxygenase 2 (metabolism)
• Depression, Chemical
• Dose-Response Relationship, Drug
• Hepatocytes (enzymology, metabolism)
• Lipopolysaccharides (adverse effects, antagonists & inhibitors)
• Liver Cirrhosis (drug therapy, etiology)
• Liver Diseases (drug therapy, etiology)
• Mice, Inbred C57BL
• Nitric Oxide Synthase Type II (metabolism)
• Oxidative Stress (drug effects)
• Protein Serine-Threonine Kinases (physiology)
• Reactive Oxygen Species (metabolism)
• Signal Transduction (drug effects, genetics, physiology)
• Triterpenes (pharmacology, therapeutic use)
• Ursolic Acid