title: Compound K modulates fatty acid-induced lipid droplet formation and expression of proteins involved in lipid metabolism in hepatocytes.
abstract: OBJECTIVE
  A key factor in the development of type 2 diabetes and non-alcoholic fatty liver disease (NAFLD) is hepatic steatosis. Incubation of human hepatic cells with free fatty acids (FFAs) causes accumulation of neutral lipids in lipid droplets (LDs) and serves as a model for hepatic steatosis. Ginsenosides, active constituents of ginsengs, have demonstrated beneficial effects in various pharmacological areas, including diabetes, however their effect on lipid accumulation in hepatocytes remains unclear. Here, we examine the effect of compound K (ComK), an active metabolite of ginsenosides, on the regulation of LD formation and on the expression of proteins involved in lipid homeostasis in hepatocytes.
  
  
  METHODS
  HuH7 cells were pretreated with ComK, followed by lipid loading with FFA. LDs were visualized using Oil Red O staining and immunohistochemistry for the LD-related protein PLIN2. Triglyceride levels were determined in isolated LDs. The expression of proteins involved in lipid homeostasis was examined by Western blotting.
  
  
  RESULTS
  Treatment with ComK significantly decreased LD formation in FFA-loaded HuH7 cells and increased phosphorylation levels of AMPK, and its substrate ACC. ComK also increased protein expression of peroxisome proliferator-activated receptor-α (PPAR-α) and acyl-CoA oxidase (ACOX1) together with elevated activity of a PPAR-α response element reporter construct. These effects were inhibited by the PPAR-α antagonist MK886.
  
  
  CONCLUSIONS
  ComK reduced LD formation and TG accumulation in FFA-loaded hepatocytes, in part by up-regulating AMPK activity and PPAR-α related pathways. These results suggest that ComK may have efficacy for the treatment of hepatic steatosis and associated diseases.
authors.affiliation: Faculty of Pharmacy, The University of Sydney, Sydney, NSW, Australia.
authors.forename: Moon-Sun
authors.initials: MS
authors.lastname: Kim
authors.forename: Kyoung-Tae
authors.initials: KT
authors.lastname: Lee
authors.forename: Tristan J
authors.initials: TJ
authors.lastname: Iseli
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Hoy
authors.forename: Jacob
authors.initials: J
authors.lastname: George
authors.forename: Thomas
authors.initials: T
authors.lastname: Grewal
authors.forename: Basil D
authors.initials: BD
authors.lastname: Roufogalis
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000704:Analysis of Variance; D001391:Azo Compounds; D015153:Blotting, Western; D002460:Cell Line; D005227:Fatty Acids / Q000378:metabolism*; D005234:Fatty Liver / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology*; D036145:Ginsenosides / Q000494:pharmacology*; D022781:Hepatocytes / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D007211:Indoles; D050356:Lipid Metabolism / Q000187:drug effects / Q000502:physiology*; D047493:PPAR alpha / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D014280:Triglycerides / Q000378:metabolism; D002722:Chlorobenzenes
chemical_list: D055372:AMP-Activated Protein Kinases; D001391:Azo Compounds; D005227:Fatty Acids; D036145:Ginsenosides; D007211:Indoles; D047493:PPAR alpha; D014280:Triglycerides; C060893:MK-886; D002722:Chlorobenzenes; C112772:ginsenoside compound K; C011049:oil red O
keywords: 5′-AMP-activated protein kinase; Compound K; acyl-CoA oxidase 1; ginsenoside metabolite; hepatic steatosis; lipid droplets; non-alcoholic fatty liver disease; peroxisome proliferator-activated receptor-α