Role of death receptors in the regulation of hepatocyte proliferation and apoptosis during rat liver regeneration.

The balance between hepatocyte proliferation and apoptosis is critical for liver homeostasis during liver regeneration. We created a rat liver regeneration model by partial hepatectomy (PH) to investigate the overall mechanism that regulates the proliferation and apoptosis of hepatocytes. The Rat Genome 230 2.0 Array was used to investigate changes in the expression levels of genes associated with the known proliferation or apoptosis signaling pathways. Ingenuity Pathway Analysis 9.0 was used to determine interactions among these signaling pathways. The results revealed that the expression levels of multiple key genes in three death receptor (DR) pathways, Fas/FasL, TNFR/TNFα, and DR6, were significantly altered in hepatocytes after PH. The expression level of the gene encoding DR6 increased by over 100-fold, whereas the levels of the genes encoding Fas, FasL, and TNFα were increased by 2-4-fold 12 h after PH. Fas/FasL, TNFR/TNFα, and DR6 are known to participate in numerous cellular events including cell proliferation and apoptosis. Our results suggest that the DR6 pathway plays a major role in the regulation of hepatocyte apoptosis, whereas Fas/FasL and TNFR/TNFα pathways may have roles in coordinating signaling activities between proliferation and apoptosis.