Published! Recent Advances on Understanding Acute Liver Failure

(by Johnny Li) Each month we will review/feature an article published by one of our very own MBP students in the biology and/or physics stream.

This article features the research of Aditya Murthy from Dr. Rama Khokha’s group [Link to Paper].

This research work focuses on fulminant hepatitis or acute liver failure, which is commonly induced by drugs such as paracetamol (acetaminophen) overdose and tetracycline, excessive alcohol intake, acute fatty liver during pregnancy, and viral hepatitis. Previous studies indicate that the establishment of fulminant hepatitis involves the cell death receptor Fas. Fas activation can both trigger hepatocyte apoptosis and hepatoprotective signals, dictating the survival or failure of the liver, and thus the organism. Engagement of this death receptor-mediated apoptosis in the liver is, however, a rather complex signaling network. Literature evidence suggests that tumor necrosis factor (TNF) signaling plays an important role in Fas-mediated fulminant hepatitis, though our knowledge on this is limited and incomplete. Additionally, the role of epidermal growth factor receptor (EGFR) signaling in acute hepatic stress is controversial.

Ectodomain shedding is a process that liberates TNF, its receptors, and several EGFR ligands from cell surface via enzymatic cleavage by A Disintegrin And Metalloproteinase 17 (ADAM17). This shedding of EGFR ligands from the cell surface is required for EGFR activation. It is known that tissue inhibitor of metalloproteinase 3 (TIMP3) inhibits ADAM17 activity, and thus provides a checkpoint control on TNF-mediated stress response. Therefore, there is a need to study the stromal control of ectodomain shedding during Fas-mediated fulminant hepatitis. This work demonstrates in vivo for the first time that TNF triggers hepatocytes to undergo Fas-mediated cell death. Interestingly, it also shows that increased TNF receptor 1 (TNFR1) shedding can protect TIMP3 knockout mice from fulminant hepatitis via diminishing TNF activation of JNK, NF-κB, and caspases. Additionally, this article identifies TIMP3 to negatively regulate EGFR-mediated phosphorylation of extracellular signal-regulated kinase (ERK1/2) or hepatoprotection.

Overall, this research highlights the importance of TIMP3 regulation of ectodomain shedding on the cell death response during fulminant hepatitis, and was recently published in The Journal of Clinical Investigation.