title: Rosmarinic acid and baicalin epigenetically derepress peroxisomal proliferator-activated receptor γ in hepatic stellate cells for their antifibrotic effect.
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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Southern California Research Center for ALPD and Cirrhosis and Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
authors.forename: Melissa D
authors.initials: MD
authors.lastname: Yang
authors.forename: Yi-Ming
authors.initials: YM
authors.lastname: Chiang
authors.forename: Reiichi
authors.initials: R
authors.lastname: Higashiyama
authors.forename: Kinji
authors.initials: K
authors.lastname: Asahina
authors.forename: Derek A
authors.initials: DA
authors.lastname: Mann
authors.forename: Jelena
authors.initials: J
authors.lastname: Mann
authors.forename: Clay C C
authors.initials: CC
authors.lastname: Wang
authors.forename: Hidekazu
authors.initials: H
authors.lastname: Tsukamoto
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D002934:Cinnamates / Q000494:pharmacology* / Q000627:therapeutic use; D053630:Depsides / Q000494:pharmacology* / Q000627:therapeutic use; D004195:Disease Models, Animal; D004365:Drugs, Chinese Herbal / Q000494:pharmacology / Q000627:therapeutic use; D044127:Epigenesis, Genetic / Q000502:physiology*; D005419:Flavonoids / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects; D055166:Hepatic Stellate Cells / Q000187:drug effects* / Q000378:metabolism* / Q000473:pathology; D008103:Liver Cirrhosis / Q000188:drug therapy / Q000473:pathology* / Q000517:prevention & control; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000378:metabolism; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism; D000097123:Rosmarinic Acid
chemical_list: D002934:Cinnamates; D053630:Depsides; D004365:Drugs, Chinese Herbal; D005419:Flavonoids; D016328:NF-kappa B; D047495:PPAR gamma; D051153:Wnt Proteins; D000097123:Rosmarinic Acid; C415597:Yang-Gan-Wan; C038044:baicalin
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