澳门威斯尼斯人网址,澳门威斯尼斯人58404

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TGF-β1/p65/MAT2A pathway regulates liver fibrogenesis via intracellular SAM

2019-04-17 澳门威斯尼斯人网址,澳门威斯尼斯人58404
Background: Hepatic stellate cell (HSC) activation induced by transforming growth factor β1 (TGF-β1) plays apivotal role in fibrogenesis, while the complex downstream mediators of TGF-β1 in such process are largely unknown.
Methods: We performed pharmacoproteomic profiling of the mice liver tissues fromcontrol, carbon tetrachloride(CCl4)-induced fibrosis and NPLC0393 administrated groups. The target gene MAT2A was overexpressed or knocked down in vivo by tail vein injection of AAV vectors. We examined NF-κB transcriptional activity on MAT2A promoter via luciferase assay. Intracellular SAM contents were analyzed by LC-MS method.
Findings: We found that methionine adenosyltransferase 2A (MAT2A) is significantly upregulated in the CCl4-induced fibrosis mice, and application of NPLC0393, a known small molecule inhibitor of TGF-β1 signaling pathway, inhibits the upregulation ofMAT2A. Mechanistically, TGF-β1 induces phosphorylation of p65, i.e., activation of NF-κB, thereby promoting mRNA transcription and protein expression of MAT2A and reduces Sadenosylmethionine (SAM) concentration in HSCs. Consistently, in vivo and in vitro knockdown of MAT2A alleviates CCl4- and TGF-β1-induced HSC activation, whereas in vivo overexpression of MAT2A facilitates hepatic fibrosis and abolishes therapeutic effect of NPLC0393.
Interpretation: This study identifies TGF-β1/p65/MAT2A pathway that is involved in the regulation of intracellular SAM concentration and liver fibrogenesis, suggesting that this pathway is a potential therapeutic target for hepatic fibrosis.

EBioMedicine. doi.org/10.1016/j.ebiom.2019.03.058.
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