title: An active metabolite of oltipraz (M2) increases mitochondrial fuel oxidation and inhibits lipogenesis in the liver by dually activating AMPK.
abstract: OBJECTIVE
  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).
  
  
  METHODS
  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.
  
  
  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.
  
  
  CONCLUSIONS
  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.affiliation: College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Korea.
authors.forename: Tae Hyun
authors.initials: TH
authors.lastname: Kim
authors.forename: Jeong Sik
authors.initials: JS
authors.lastname: Eom
authors.forename: Chan Gyu
authors.initials: CG
authors.lastname: Lee
authors.forename: Yoon Mee
authors.initials: YM
authors.lastname: Yang
authors.forename: Yong Sup
authors.initials: YS
authors.lastname: Lee
authors.forename: Sang Geon
authors.initials: SG
authors.lastname: Kim
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D016588:Anticarcinogenic Agents / Q000378:metabolism / Q000494:pharmacology; D000975:Antioxidants / Q000494:pharmacology*; D059305:Diet, High-Fat; D004789:Enzyme Activation; D005234:Fatty Liver / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D056945:Hep G2 Cells; D006801:Humans; D050356:Lipid Metabolism / Q000187:drug effects; D050155:Lipogenesis / Q000187:drug effects*; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D000071518:Liver X Receptors; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D057093:Orphan Nuclear Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000187:drug effects; D011719:Pyrazines / Q000378:metabolism / Q000494:pharmacology*; D051780:Sterol Regulatory Element Binding Protein 1 / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D013871:Thiones; D013876:Thiophenes
chemical_list: D000893:Anti-Inflammatory Agents; D016588:Anticarcinogenic Agents; D000975:Antioxidants; D000071518:Liver X Receptors; C000605213:NR1H3 protein, human; C000605214:Nr1h3 protein, mouse; D057093:Orphan Nuclear Receptors; D011719:Pyrazines; D051780:Sterol Regulatory Element Binding Protein 1; D013871:Thiones; D013876:Thiophenes; C026209:oltipraz; D055372:AMP-Activated Protein Kinases