MKL1 promotes endothelial-to-mesenchymal transition and liver fibrosis by activating TWIST1 transcription.

Abstract:

:Excessive fibrogenic response in the liver disrupts normal hepatic anatomy and function heralding such end-stage liver diseases as hepatocellular carcinoma and cirrhosis. Sinusoidal endothelial cells contribute to myofibroblast activation and liver fibrosis by undergoing endothelial-mesenchymal transition (EndMT). The underlying mechanism remains poorly defined. Here we report that inhibition or endothelial-specific deletion of MKL1, a transcriptional modulator, attenuated liver fibrosis in mice. MKL1 inhibition or deletion suppressed EndMT induced by TGF-β. Mechanistically, MKL1 was recruited to the promoter region of TWIST1, a master regulator of EndMT, and activated TWIST1 transcription in a STAT3-dependent manner. A small-molecule STAT3 inhibitor (C188-9) alleviated EndMT in cultured cells and bile duct ligation (BDL) induced liver fibrosis in mice. Finally, direct inhibition of TWIST1 by a small-molecule compound harmine was paralleled by blockade of EndMT in cultured cells and liver fibrosis in mice. In conclusion, our data unveil a novel mechanism underlying EndMT and liver fibrosis and highlight the possibility of targeting the STAT3-MKL1-TWIST1 axis in the intervention of aberrant liver fibrogenesis.

journal_name

Cell Death Dis

journal_title

Cell death & disease

authors

Li Z,Chen B,Dong W,Kong M,Fan Z,Yu L,Wu D,Lu J,Xu Y

doi

10.1038/s41419-019-2101-4

subject

Has Abstract

pub_date

2019-11-27 00:00:00

pages

899

issue

12

issn

2041-4889

pii

10.1038/s41419-019-2101-4

journal_volume

10

pub_type

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