The natural carotenoid astaxanthin, a PPAR-α agonist and PPAR-γ antagonist, reduces hepatic lipid accumulation by rewiring the transcriptome in lipid-loaded hepatocytes

Mol Nutr Food Res. 2012 Jun;56(6):878-88. doi: 10.1002/mnfr.201100798.


Scope: A natural carotenoid abundant in seafood, astaxanthin (AX), has hypolipidemic activity, but its underlying mechanisms of action and protein targets are unknown. We investigated the molecular mechanism of action of AX in hepatic hyperlipidemia by measuring peroxisome proliferator-activated receptors (PPAR) activity.

Methods and results: We examined the binding of AX to PPAR subtypes and its effects on hepatic lipid metabolism. AX binding activated PPAR-α, but inhibited PPAR-γ transactivation activity in reporter gene assay and time-resolved fluorescence energy transfer analyses. AX had no effect on PPARδ/β transactivation. AX bound directly to PPAR-α and PPAR-γ with moderate affinity, as assessed by surface plasmon resonance experiments. The differential effects of AX on PPARs were confirmed by measuring the expression of unique responsive genes for each PPAR subtype. AX significantly reduced cellular lipid accumulation in lipid-loaded hepatocytes. Transcriptome analysis revealed that the net effects of stimulation with AX (100 μM) on lipid metabolic pathways were similar to those elicited by fenofibrate and lovastatin (10 μM each), with AX rewiring the expression of genes involved in lipid metabolic pathways.

Conclusion: AX is a PPAR-α agonist and PPAR-γ antagonist, reduces hepatic lipid accumulation by rewiring the transcriptome in lipid-loaded hepatocytes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antioxidants / metabolism
  • Antioxidants / pharmacology
  • CHO Cells
  • Cells, Cultured
  • Cricetinae
  • Cricetulus
  • Fluorescence Resonance Energy Transfer
  • Gene Expression Profiling
  • Genes, Reporter / drug effects
  • Hep G2 Cells
  • Hepatocytes / drug effects*
  • Hepatocytes / metabolism
  • Humans
  • Lipid Metabolism / drug effects*
  • Lipotropic Agents / metabolism
  • Lipotropic Agents / pharmacology*
  • Oligonucleotide Array Sequence Analysis
  • PPAR alpha / agonists*
  • PPAR alpha / genetics
  • PPAR alpha / metabolism
  • PPAR gamma / antagonists & inhibitors*
  • PPAR gamma / genetics
  • PPAR gamma / metabolism
  • Surface Plasmon Resonance
  • Transcriptional Activation / drug effects*
  • Xanthophylls / metabolism
  • Xanthophylls / pharmacology


  • Antioxidants
  • Lipotropic Agents
  • PPAR alpha
  • PPAR gamma
  • Xanthophylls
  • astaxanthine