Effect of GDF15 on acetaminophen (APAP)-induced liver injury in mice

Acetaminophen (APAP)-induced liver injury (AILI) has been recognized as a pivotal contributor to drug-induced liver failure in western countries, but its molecular mechanism remains poorly understood. After data mining using the Gene Expression Omnibus (GEO) database, we found that the gene expression of growth differentiation factor 15 (GDF15) increased significantly after APAP-induced hepatotoxicity in mouse liver. However, the precise role of GDF15 in AILI has yet to be clarified. To deal with this question, we first examined the temporal gene expression pattern of GDF15 after APAP treatment. Next, overexpression of hepatic GDF15 using adeno-associated virus serotype 8 (AAV8) was employed to investigate the role of GDF15 in AILI. In addition, therapeutic administration of recombinant human GDF15 (rhGDF15) was conducted to probe its curative effect after APAP overdose. We observed that protein expression of GDF15 was significantly increased after APAP overdose. However, there were no significant differences in AILI-related outcomes after overexpression or supplementation of GDF15. The contents of serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST), morphological feature of liver, the level of reduced form of glutathione (GSH), the activation of c-Jun-N-terminal kinase (JNK), the expression of genes relevant to oxidative stress and cell proliferation were not remarkably changed between AAV8-GFP and AAV8-Gdf15 groups. Although the liver injury was not improved by rhGDF15 administration, the gene expression levels of glutamate-cysteine ligase modifier subunit (Gclm) and glutamate-cysteine ligase catalytic subunit (Gclc) which function downstream of Nrf2 signaling pathway were significantly increased. Altogether, despite a noticeable elevated expression after APAP overdose, GDF15 overexpression or supplementation exerted no significant ameliorative effect on AILI. Further mechanism and consequence of Gclm and Gclc elevation by GDF15 remains to be elucidated.