Document Detail


An active metabolite of oltipraz (M2) increases mitochondrial fuel oxidation and inhibits lipogenesis in the liver by dually activating AMPK.
MedLine Citation:
PMID:  23145499     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
BACKGROUND AND PURPOSE: Oltipraz, a cancer chemopreventive agent, has an anti-steatotic effect via liver X receptor-α (LXRα) inhibition. Here we have assessed the biological activity of a major metabolite of oltipraz (M2) against liver steatosis and steatohepatitis and the underlying mechanism(s).
EXPERIMENTAL APPROACH: Blood biochemistry and histopathology were assessed in high-fat diet (HFD)-fed mice treated with M2. An in vitroHepG2 cell model was used to study the mechanism of action. Immunoblotting, real-time PCR and luciferase reporter assays were performed to measure target protein or gene expression levels.
KEY RESULTS: M2 treatment inhibited HFD-induced steatohepatitis and diminished oxidative stress in liver. It increased expression of genes encoding proteins involved in mitochondrial fuel oxidation. Mitochondrial DNA content and oxygen consumption rate were enhanced. Moreover, M2 treatment repressed activity of LXRα and induction of its target genes, indicating anti-lipogenic effects. M2 activated AMP-activated protein kinase (AMPK). Inhibition of AMPK by over-expression of dominant negative AMPK (DN-AMPK) or by Compound C prevented M2 from inducing genes for fatty acid oxidation and repressed sterol regulatory element binding protein-1c (SREBP-1c) expression. M2 activated liver kinase B1 (LKB1) and increased the AMP/ATP ratio. LKB1 knockdown failed to reverse target protein modulations or AMPK activation by M2, supporting the proposal that both LKB1 and increased AMP/ATP ratio contribute to its anti-steatotic effect.
CONCLUSION AND IMPLICATIONS: M2 inhibited liver steatosis and steatohepatitis by enhancing mitochondrial fuel oxidation and inhibiting lipogenesis. These effects reflected activation of AMPK elicited by increases in LKB1 activity and AMP/ATP ratio.
Authors:
Tae Hyun Kim; Jeong Sik Eom; Chan Gyu Lee; Yoon Mee Yang; Yong Sup Lee; Sang Geon Kim
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  British journal of pharmacology     Volume:  168     ISSN:  1476-5381     ISO Abbreviation:  Br. J. Pharmacol.     Publication Date:  2013 Apr 
Date Detail:
Created Date:  2013-03-15     Completed Date:  2013-11-25     Revised Date:  2014-04-01    
Medline Journal Info:
Nlm Unique ID:  7502536     Medline TA:  Br J Pharmacol     Country:  England    
Other Details:
Languages:  eng     Pagination:  1647-61     Citation Subset:  IM    
Copyright Information:
© 2012 The Authors. British Journal of Pharmacology © 2012 The British Pharmacological Society.
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MeSH Terms
Descriptor/Qualifier:
AMP-Activated Protein Kinases / metabolism*
Animals
Anti-Inflammatory Agents / pharmacology*
Anticarcinogenic Agents / metabolism,  pharmacology
Antioxidants / pharmacology*
Diet, High-Fat
Enzyme Activation
Fatty Liver / drug therapy,  metabolism,  pathology
Hep G2 Cells
Humans
Lipid Metabolism / drug effects
Lipogenesis / drug effects*
Liver / drug effects*,  metabolism
Male
Mice
Mice, Inbred C57BL
Mitochondria / drug effects*,  metabolism
Orphan Nuclear Receptors / antagonists & inhibitors*,  metabolism
Oxidation-Reduction
Oxidative Stress / drug effects
Pyrazines / metabolism,  pharmacology*
Sterol Regulatory Element Binding Protein 1 / genetics,  metabolism,  pharmacology
Chemical
Reg. No./Substance:
0/Anti-Inflammatory Agents; 0/Anticarcinogenic Agents; 0/Antioxidants; 0/Orphan Nuclear Receptors; 0/Pyrazines; 0/Sterol Regulatory Element Binding Protein 1; 0/liver X receptor; 6N510JUL1Y/oltipraz; EC 2.7.11.1/AMP-Activated Protein Kinases
Comments/Corrections

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