Rosmarinic acid and baicalin epigenetically derepress peroxisomal proliferator-activated receptor γ in hepatic stellate cells for their antifibrotic effect.
Rosmarinic acid and baicalin epigenetically derepress peroxisomal proliferator-activated receptor γ in hepatic stellate cells for their antifibrotic effect.
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DOI：
10.1002/hep.24792
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发表时间：
2012-04
期刊：
影响因子：
13.5
通讯作者：
Tsukamoto, Hidekazu
中科院分区：
文献类型：
--
作者：
Yang, Melissa D.;Chiang, Yi-Ming;Higashiyama, Reiichi;Asahina, Kinji;Mann, Derek A.;Mann, Jelena;Wang, Clay C. C.;Tsukamoto, Hidekazu
肝星状细胞（HSC）经历成肌纤维细胞转分化（活化）以参与肝纤维化，并且鉴定这种细胞命运调节的分子靶点对于开发针对该疾病的有效治疗模式是必不可少的。过氧化物酶体增殖物激活受体γ（Peroxisomal proliferator-activated receptor γ，PPARγ）是HSC分化所必需的，其表观遗传抑制是HSC活化的基础。中药养肝丸（YGW）预防肝纤维化，但其活性成分和分子机制尚不清楚。在这里，我们证明YGW通过Pparγ的表观遗传去抑制来防止和逆转HSC活化，包括MeCP 2表达的减少及其向Pparγ启动子的募集，PRC 2甲基转移酶EZH 2的表达的抑制以及随后3'外显子处H2 K27二甲基化的减少。HPLC/MS和NMR分析确定多酚迷迭香酸（RA）和黄芩苷（BC）作为活性植物化合物。RA和BC抑制典型Wnt的表达和信号传导，其涉及上述Pparγ表观遗传抑制。RA治疗存在胆汁淤积性肝纤维化的小鼠可抑制HSC活化和肝纤维化进展。总之，这些结果证明了YGW及其活性组分RA和BC通过抑制HSC中的经典Wnt信号传导介导的Pparγ去抑制来治疗肝纤维化的潜力。
Hepatic stellate cells (HSCs) undergo myofibroblastic trans-differentiation (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 via epigenetic de-repression of Pparγ involving reductions in MeCP2 expression and its recruitment to Pparγ promoter, suppressed expression of PRC2 methyltrasferase EZH2 and consequent reduction of H2K27di-methylation at the 3’ exon. HPLC/MS and 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. In conclusion, these results demonstrate a therapeutic potential of YGW and its active component RA and BC for liver fibrosis via Pparγ de-repression mediated by suppression of canonical Wnt signaling in HSCs.
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影响因子：
25.7
作者：
Cassiman, D;Barlow, A;Pachnis, V
通讯作者：
Pachnis, V
DOI：
10.1083/jcb.200908151
发表时间：
2010-04-05
期刊：
The Journal of cell biology
影响因子：
--
作者：
Szulwach KE;Li X;Smrt RD;Li Y;Luo Y;Lin L;Santistevan NJ;Li W;Zhao X;Jin P
通讯作者：
Jin P
影响因子：
21.3
作者：
Tseng, YH;Butte, AJ;Kahn, CR
通讯作者：
Kahn, CR
影响因子：
14.8
作者：
Bok, Jin Woo;Chiang, Yi-Ming;Szewczyk, Edyta;Reyes-Domingez, Yazmid;Davidson, Ashley D.;Sanchez, James F.;Lo, Hsien-Chun;Watanabe, Kenji;Strauss, Joseph;Oakley, Berl R.;Wang, Clay C. C.;Keller, Nancy P.
通讯作者：
Keller, Nancy P.
影响因子：
13.5
作者：
Asahina, Kinji;Tsai, Shirley Y.;Li, Peng;Ishii, Mamoru;Maxson, Robert E., Jr.;Sucov, Henry M.;Tsukamoto, Hidekau
通讯作者：
Tsukamoto, Hidekau