Protective effect of resveratrol derivatives on high-fat diet induced fatty liver by activating AMP-activated protein kinase

Arch Pharm Res. 2014;37(9):1169-76. doi: 10.1007/s12272-014-0347-z. Epub 2014 Mar 18.


Non-alcoholic fatty liver disease is associated with inhibited AMP-activated kinase (AMPK) and activation of sterol regulatory element binding protein 1 (SREBP-1). AMPK phosphorylation inhibits SREBP-1, a major transcription factor of de novo lipogenesis, by inhibiting the liver X receptor (LXR) or by direct phosphorylation. Resveratrol, a polyphenol, has regulatory effects on hepatic lipid metabolism as a potent AMPK activator. In this study, we evaluated the anti-steatogenic effects of resveratrol and its derivatives and identified the molecular mechanism in vitro and in vivo. Resveratrol and its derivatives decreased lipid accumulation by free fatty acids (FFA mixture; 0.5 mM, oleic acid:palmitic acid = 2: 1) in H4IIEC3 cells. Synthesized derivatives of resveratrol had lower cytotoxicity than the parental molecule with similar potency. SY-102 suppressed SREBP-1 maturation by T0901317, an LXR agonist, and decreased SRE luciferase activity and the mRNA levels of lipogenic genes. Inhibition of AMPK by pre-treatment with compound C completely blocked the effects of SY-102. To evaluate their efficacy in vivo, mice were fed a high-fat diet for 5 days, and resveratrol or SY-102 was administered orally for the last 2 days. Oral administration of the SY-102 increased AMPK phosphorylation, followed by reduced hepatic triglyceride accumulation to a similar extent as resveratrol. These data demonstrate that SY-102, a synthesized derivative of resveratrol, might provide a promising therapeutic effect against fatty liver disease.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • AMP-Activated Protein Kinases / chemistry
  • AMP-Activated Protein Kinases / metabolism*
  • Animals
  • Cell Line
  • Cell Survival / drug effects
  • Enzyme Activation / drug effects
  • Fatty Acids, Nonesterified / adverse effects
  • Fatty Acids, Nonesterified / antagonists & inhibitors
  • Gene Expression Regulation / drug effects
  • Hepatocytes / drug effects*
  • Hepatocytes / enzymology
  • Hepatocytes / metabolism
  • Humans
  • Lipotropic Agents / adverse effects
  • Lipotropic Agents / pharmacology
  • Lipotropic Agents / therapeutic use*
  • Male
  • Methylation
  • Mice, Inbred ICR
  • Non-alcoholic Fatty Liver Disease / drug therapy*
  • Non-alcoholic Fatty Liver Disease / enzymology
  • Non-alcoholic Fatty Liver Disease / metabolism
  • Phosphorylation / drug effects
  • Protein Processing, Post-Translational / drug effects
  • Random Allocation
  • Rats
  • Resveratrol
  • Specific Pathogen-Free Organisms
  • Stilbenes / adverse effects
  • Stilbenes / chemistry
  • Stilbenes / pharmacology
  • Stilbenes / therapeutic use*


  • Fatty Acids, Nonesterified
  • Lipotropic Agents
  • SY-102
  • Stilbenes
  • AMP-Activated Protein Kinases
  • Resveratrol