Hepatic upregulation of fetuin-A mediates acetaminophen-induced liver injury through activation of TLR4 in mice

Abstract

Acetaminophen (APAP)-induced liver injury (AILI) is initiated by the generation of a reactive metabolite and ultimately leads to hepatocyte necrosis. Necrotic cells secrete damage-associated molecular patterns that activate hepatic nonparenchymal cells and induce an inflammatory response. Fetuin-A is a hepatokine with reported involvement in low-grade inflammation in many diseases, due to acting as an endogenous ligand for TLR4. However, little is known about the role of fetuin-A in AILI. In this study, we showed that fetuin-A is involved in the aggravation of hepatotoxicity during the initial phase of AILI progression. Treatment with APAP increased the expression and serum levels of fetuin-A in mice. Fetuin-A upregulated transcription of pro-inflammatory cytokines and chemokines through activation of TLR4 and also increased monocyte infiltration into the liver, leading to necroinflammatory reactions in AILI. However, these reactions were attenuated with the silencing of fetuin-A using adenoviral shRNA. As a result, mice with silenced fetuin-A exhibited less centrilobular necrosis and liver injury compared to controls in response to APAP. In conclusion, our results suggest that fetuin-A is an important hepatokine that mediates the hepatotoxicity of APAP through production of chemokines and thus regulates the infiltration of monocytes into the liver, a critical event in the inflammatory response during the initial phase of AILI. Our results indicate that a strategy based on the antagonism of fetuin-A may be a novel therapeutic approach to the treatment of acetaminophen-induced acute liver failure.

Keywords: Acetaminophen; Chemokine; Fetuin-A; Hepatokine; Hepatotoxicity.