Serum amyloid A1 induces apoptosis and cell survival in hepatocytes following acute liver injury

Background: Acute phase protein serum amyloid A (SAA) is one of abundantly expressed protein in the liver following injury or other traumas. However, the relative contribution during inflammatory response in the liver remains largely elusive. Method: SAA1 genetic knockdown was performed by injecting siRNA/invivofectamine3.0 complex in CCl 4 -treated C57BL/6 mice. Parts of the excised liver were then processed for histological analyses. Primary human hepatocytes were isolated from surgical specimens, and evaluated for cell death, luciferase activity and chemokine production after recombinant human SAA1 treatment. Results: In a mild liver injury status, after hepatocyte specific knockdown of SAA1 in mice liver, we observed reduced number of apoptotic hepatocyte at non-necrotic area. In vitro cell death assay revealed that in primary human hepatocytes, SAA1 induced apoptosis and cell survival simultaneously. SAA1 induced activation of phosphatidylinositol 3-kinase (PI3K), Akt and nuclear factor κB (NF-κB) - dependent genes, which ultimately led to cell survival. In contrast, blockade of NF-κB revealed hepatotoxic effects of SAA1 with appearance of apoptotic signatures such as caspase-3 and PARP cleavage products. SAA1-induced expression of pro-inflammatory genes such as MCP-1 and RANTES were inhibited when two survival signals NF-κB and PI3K were pharmacologically blocked by treatment with ActD and LY294002, respectively. Conclusion: These results indicate that cytokine-like property of SAA1 resembles TNF-α signaling pathway in hepatocytes and triggers apoptosis and cell survival responding to injury.