p53-insensitive PUMA down-regulation is essential in the early phase of liver regeneration after partial hepatectomy in mice

Background & Aims: Liver regeneration after partial hepatectomy involve proliferation and apoptosis of hepatocytes. PUMA, the well-known proapoptotic member of the Bcl-2 family, can respond to distinct stimuli. This study explores the role of PUMA and its relationship with other Bcl-2 family members in this process. Methods: The expression patterns of PUMA and its related proteins were investigated in livers after 70% hepatectomies. The contributions of PUMA to liver regeneration were assessed by manipulating its expression levels using adenovirus vectors. The differences in PUMA expression levels in human normal livers and hepatitis, as well as hepatoma tissues were characterised. Results: During the first 72 h after hepatectomy, PUMA was highly down-regulated transcriptionally, while the levels of p53, Slug, Bax, and Bcl-X-L proteins increased continuously. Highly induced expression of PUMA in the liver by Ad-PUMA caused lethal fulminant hepatitis 48 h after treatment. Slightly induced expression was enough to impair liver regeneration, with an elevation of post-hepatectomy mortality, an increase of apoptosis, a decrease of proliferation, an up-regulation of Bax levels, an induction of inflammatory chemokines (KC and macrophage inflammatory protein-2), and an increase in the neutrophil infiltration relative to the control. In contrast to the results from the regenerating liver, PUMA expression showed an increased trend in human hepatitis and hepatoma tissues. Conclusions: Sharply p53-insensitive down-regulation of PUMA, coupled with Bcl-X-L up-regulation, may play a cytoprotective role in liver regeneration after hepatectomy. Furthermore, the increased expression of PUMA in hepatitis and hepatoma may indicate misregulation of the apoptotic network in these diseases. (c) 2010 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.