Hope for liver failure patients

17 Jun 2016. NUS scientists have identified the protein MOAP-1 as a potential treatment target for acute liver failure triggered by activation of a cell suicide program.

Apoptosis, is a physiological process to eliminate damaged and harmful cells through activation of a cell suicide programme to prevent these cells from spreading harmful effect to healthy cells. The death receptor Fas is an initiator for the suicide programme in the liver. A team led by Prof Victor YU from the Department of Pharmacy in NUS discovered that Fas is critically dependent on MOAP-1 to execute the death programme. Their research showed that mice with the MOAP-1 gene removed from the genome are completely resistant to developing acute liver failure caused by the activation of the Fas receptor.

Improper activation or deactivation of the cell suicide programme mediated by Fas signalling has been linked to many liver diseases. This team and others previously demonstrated that MOAP-1 has a role in facilitating the activation of the suicide programme in cell lines, but its in vivo function has never been studied. The team has developed a genetically modified mouse with the MOAP-1 gene removed to allow them to study the physiological functions of the MOAP-1 gene. The mice without the MOAP-1 gene were found to be completely resistant to developing acute liver failure and lethality triggered by activation of Fas.

Prof Yu’s work demonstrates the essential role of MOAP-1 in the execution of the Fas-induced cell death programme in the liver. This opens up many exciting opportunities for research towards elucidating the roles of MOAP-1 in regulating liver function and modulating the development of liver diseases caused by hyper or hypo activity of the Fas signalling system. The levels of MOAP-1 protein in cells are regulated by the enzyme-linked processes via the ubiquitination and de-ubiquitination mechanisms which raise hope that MOAP-1 is a potential target for drug development.

The research team intends to further explore the roles of MOAP-1 in regulating the physiological functions of the liver and to study its effect on the pathological development of certain liver diseases. Specifically, they will undertake studies to examine the roles of MOAP-1 in acute liver failures which are triggered by different classes of liver toxins. They will also be studying the roles of MOAP-1 in liver cancer development. As MOAP-1 is regulated by enzyme-linked mechanisms, cell-based screens can be devised to identify small chemical compounds that can modulate protein levels of MOAP-1 in the liver.

Figure shows that toxic insult to the liver such as ingestion of liver sensitive poisonous substances can trigger massive activation of the cell suicide programme which in turn will lead to acute liver failure and lethality. The cell suicide programme in the liver can be blocked by deleting the MOAP-1 gene from the mice. This suggests that inhibition of MOAP-1 activity by drugs could be a viable therapeutic approach for blocking development of acute liver failure triggered by activation of the cell suicide programme. [Image by Chong Teik TAN]

This research is supported by the Singapore Ministry of Health’s National Medical Research Council under its Individual Research Grant (NMRC/1317/2011).

Reference

Tan C., Zhou Q., Su Y., Fu N., Chang H., Tao R., Sukumaran S., Baksh S., Tan Y., Sabapathy K., Yu C., Yu V. “MOAP-1 Mediates Fas-induced Apoptosis in Liver by Facilitating tBid Recruitment to Mitochondria”. Cell Reports (2016). doi 10.1016/j.celrep.2016.05.068.