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.
Highlights
Liver fibrosis is generally perceived as a host defense mechanism following liver injury
We have previously shown that germline deletion of Megakaryocytic leukemia 1 (MKL1) ameliorates liver fibrosis in mice[20,21]
Both wild type (WT) and ecKOm/m mice were subjected to bile duct ligation to induce liver fibrosis
Summary
Liver fibrosis is generally perceived as a host defense mechanism following liver injury. Uptake of excessive nutrition, infection of pathogens, and exposure to hepatotoxic substances, fibrogenesis reins in liver damage, facilitates wound closure, and safeguards the structural and functional integrity of the liver. Uncontrolled and/or unresolved liver fibrosis, serves to disrupt normal liver structure, is associated with loss of critical key liver functions, and heralds such end-stage liver diseases as hepatocellular carcinoma and cirrhosis[1,2]. EndMT is a developmentally pivotal process key to organogenesis[10]. Post-embryonic EndMT more often than not correlates with the onset of a wide range of human diseases. During EndMT, endothelial cells switch from a Official journal of the Cell Death Differentiation Association
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