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

Lookup NU author(s): Professor Derek Mann, Professor Jelena Mann

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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 ? (PPAR?) 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 Ppar? involving reductions in MeCP2 expression and its recruitment to Ppar? 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 Ppar? 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 Ppar? derepression mediated by suppression of canonical Wnt signaling in HSCs. (Hepatology 2012)

Publication metadata

Author(s): Yang MD, Chiang YM, Higashiyama R, Asahina K, Mann DA, Mann J, Wang CCC, Tsukamoto H

Publication type: Article

Publication status: Published

Journal: Hepatology

Year: 2012

Volume: 55

Issue: 4

Pages: 1271-1281

Print publication date: 01/04/2012

ISSN (print): 0270-9139

ISSN (electronic): 1527-3350

Publisher: John Wiley & Sons, Inc.

URL: http://dx.doi.org/10.1002/hep.24792

DOI: 10.1002/hep.24792

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