C/EBP-α Promotes Mitochondrial Fission and Inhibits the Activation of Hepatic Stellate Cells via YAP-Drp1 Pathway.

Abstract

The activation of hepatic stellate cells (HSCs) plays a key role in the pathogenesis of liver fibrosis. However, the activation of HSCs requires energy from mitochondria-highly dynamic organelles. In our previous studies, we have confirmed that CCAAT/enhancer binding protein α (C/EBP-α) can inhibit the activation of HSCs, but whether it can affect the activation of HSCs by regulating mitochondrial dynamics is still unclear. In this study, we characterized the roles and mechanisms of C/EBP-α-mediated mitochondrial fission in regulating HSCs activation. We found that C/EBP-α upregulates Drp1 expression through inhibiting YAP expression, thus promoting mitochondrial fission and suppressing the activation of HSCs. In addition, in the HSCs with C/EBP-α overexpression, the epistatic roles of YAP and Drp1 in regulating mitochondrial biology and HSCs activation were interrogated with their respective inhibitors/agonists. Thus, we propose that mitochondrial fission plays an important role in the activation of HSCs and fibrosis that is regulated by a C/EBP-α-YAP-Drp1 axis.