RIPK3 promoter hypermethylation in hepatocytes protects from bile acid induced inflammation and necroptosis

Abstract

Background & AimsNecroptosis facilitates cell death in a controlled manner and is employed by many cell types following injury. It plays a major role in various liver diseases, albeit the cell type-specific regulation of necroptosis in the liver and especially hepatocytes has not yet been conceptualized. Approaches & ResultsHere, we demonstrate that DNA methylation suppresses RIPK3 expression in human hepatocytes and HepG2 cells. In diseases leading to cholestasis the RIPK3 expression is induced in mice and humans in a cell-type specific manner. Over-expression of RIPK3 in HepG2 cells leads immediately to RIPK3 activation by phosphorylation that is further modulated by different bile acids. ConclusionBile acids mediated RIPK3 activation facilitates the secretion and expression of IL-8 via the JNK-pathway, suggesting hepatocytes suppress RIPK3 expression to protect themselves from bile acid induced necroptosis and inflammation but in chronical liver diseases associated with cholestasis induction of RIPK3 expression may be an early event signaling danger and repair through release of IL-8. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=92 SRC="FIGDIR/small/426790v1_ufig1.gif" ALT="Figure 1"> View larger version (28K): org.highwire.dtl.DTLVardef@1134cborg.highwire.dtl.DTLVardef@1a12063org.highwire.dtl.DTLVardef@15575a8org.highwire.dtl.DTLVardef@19f7596_HPS_FORMAT_FIGEXP M_FIG C_FIG