Demonstrating Enhanced Liver Regeneration in Mice
The liver is the most regenerative of organs in mammals, capable of regrowing much of its mass. That is arguably less important than the ability of a complete liver to regenerate the damage of aging and disease, such as growing fibrosis and dysfunction in cell populations necessary for organ function. Deployment of therapies to reliably achieve this goal still lies ahead, but researchers are making slow progress in the right direction:
The liver possesses extraordinary regenerative capacity in response to injury. However, liver regeneration is often impaired in disease conditions. Wild-type p53-induced phosphatase 1 (Wip1) is known as a tumor promoter and enhances cell proliferation mainly by deactivating anti-oncogenes. However, in this work, we identified an unexpected role of Wip1 in liver regeneration. In contrast to its known role in promoting cell proliferation in extra-hepatic tissue, we found that Wip1 suppressed hepatocyte proliferation after partial hepatectomy (PH). Deletion of Wip1 increased the rate of liver regeneration following partial hepatectomy.The enhanced liver regeneration in Wip1 deficient mice was due to the activation of mammalian target of rapamycin complex 1 (mTORC1) pathway. Furthermore, we showed that Wip1 physically interacted with and dephosphorylated mammalian target of rapamycin (mTOR). Interestingly, inhibition of Wip1 also activated p53 pathway during liver regeneration. Disruption of the p53 pathway further enhanced the liver regeneration in Wip1 deficient mice. Therefore, inhibition of Wip1 has a dual role in liver regeneration, i.e. promoting hepatocyte proliferation via activation of mTORC1 pathway, meanwhile suppressing liver regeneration through activation of p53 pathway.
For the first time we demonstrate that mTOR is a new direct target of Wip1. Wip1 inhibition can activate the mTORC1 pathway and enhance hepatocyte proliferation after hepatectomy. Therefore, our findings have clinical applications in cases where liver regeneration is critical, including acute liver failure, cirrhosis or small-for-size liver transplantations.