Rosmarinic acid and baicalin epigenetically derepress peroxisomal proliferator-activated receptor γ in hepatic stellate cells for their antifibrotic effect

Hepatology. 2012 Apr;55(4):1271-81. doi: 10.1002/hep.24792. Epub 2012 Mar 1.

Abstract

Hepatic stellate cells (HSCs) undergo myofibroblastic transdifferentiation (activation) to participate in liver fibrosis and identification of molecular targets for this cell fate regulation is essential for development of efficacious therapeutic modalities for the disease. Peroxisomal proliferator-activated receptor γ (PPARγ) is required for differentiation of HSCs and its epigenetic repression underlies HSC activation. The herbal prescription Yang-Gan-Wan (YGW) prevents liver fibrosis, but its active ingredients and molecular mechanisms are unknown. Here we demonstrate YGW prevents and reverses HSC activation by way of epigenetic derepression of Pparγ involving reductions in MeCP2 expression and its recruitment to Pparγ promoter, suppressed expression of PRC2 methyltransferase EZH2, and consequent reduction of H2K27di-methylation at the 3' exon. High-performance liquid chromatography / mass spectrometry (HPLC/MS) and nuclear magnetic resonance (NMR) analyses identify polyphenolic rosmarinic acid (RA) and baicalin (BC) as active phytocompounds. RA and BC suppress the expression and signaling by canonical Wnts, which are implicated in the aforementioned Pparγ epigenetic repression. RA treatment in mice with existing cholestatic liver fibrosis inhibits HSC activation and progression of liver fibrosis.

Conclusion: These results demonstrate a therapeutic potential of YGW and its active component RA and BC for liver fibrosis by way of Pparγ derepression mediated by suppression of canonical Wnt signaling in HSCs.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Cell Differentiation / drug effects
  • Cells, Cultured
  • Cinnamates / pharmacology*
  • Cinnamates / therapeutic use
  • Depsides / pharmacology*
  • Depsides / therapeutic use
  • Disease Models, Animal
  • Drugs, Chinese Herbal / pharmacology
  • Drugs, Chinese Herbal / therapeutic use
  • Epigenesis, Genetic / physiology*
  • Flavonoids / pharmacology*
  • Gene Expression Regulation / drug effects
  • Hepatic Stellate Cells / drug effects*
  • Hepatic Stellate Cells / metabolism*
  • Hepatic Stellate Cells / pathology
  • Liver Cirrhosis / drug therapy
  • Liver Cirrhosis / pathology*
  • Liver Cirrhosis / prevention & control
  • Male
  • Mice
  • Mice, Inbred C57BL
  • NF-kappa B / metabolism
  • PPAR gamma / genetics
  • PPAR gamma / metabolism*
  • Rats
  • Rats, Wistar
  • Signal Transduction / drug effects
  • Signal Transduction / physiology
  • Wnt Proteins / genetics
  • Wnt Proteins / metabolism

Substances

  • Cinnamates
  • Depsides
  • Drugs, Chinese Herbal
  • Flavonoids
  • NF-kappa B
  • PPAR gamma
  • Wnt Proteins
  • Yang-Gan-Wan
  • baicalin
  • rosmarinic acid