Abstract
Inflammation plays a critical role in disease pathogenesis of acute-on-chronic liver failure (ACLF). Atg13 is a vital regulatory component of ULK1 complex, which plays an essential role in initiation of autophagy, and autophagy has been connected to hepatic inflammation. The aim of this study is to evaluate how autophagy regulates hepatic stellate cells (HSCs) inflammatory responses via Atg13 during ACLF. Clinical data were collected from ACLF patients, and surgical resected paraffin embedded human ACLF liver tissues specimens were collected. Inflammation and autophagy were investigated by immunoblot analysis in HSCs treated with lipopolysaccharide (LPS). Co-immunoprecipitation were used to investigate interaction of Atg13 and ULK1. Our data exhibit that serum LPS is positively associated with disease severity in ACLF patients, and p38 MAPK is overexpressed in ACLF liver tissues. Inflammatory factors are up-regulated via the activation of p38 MAPK and the inhibition of the autophagy in LX-2 cells. Furthermore, we illuminate in the vitro study that LPS triggers p38 MAPK activity, resulting in phosphorylation of Atg13, inhibition of Atg13-ULK1 interaction and autophagy. This study highlights a molecular mechanism that LPS promotes inflammation through inhibition of autophagy in HSCs via Atg13, and provides a new understanding into the mechanistic of inflammatory process of severe hepatitis and a novel strategy for ACLF treatment.
p38-MAPK- and caspase-3-mediated superoxide-induced apoptosis of rat hepatic stellate cells: Reversal by retinoic acid
