A20 protects mice from lethal radical hepatectomy by promoting hepatocyte proliferation via a p21waf1-dependent mechanism.
The liver has a remarkable regenerative capacity, allowing recovery following injury. Regeneration after injury is contingent on maintenance of healthy residual liver mass, otherwise fulminant hepatic failure (FHF) may arise. Understanding the protective mechanisms safeguarding hepatocytes and promoting their proliferation is critical for devising therapeutic strategies for FHF. We demonstrate that A20 is part of the physiological response of hepatocytes to injury. In particular, A20 is significantly upregulated in the liver following partial hepatectomy. A20 protects hepatocytes from apoptosis and ongoing inflammation by inhibiting NF-kappaB. Hepatic expression of A20 in BALB/c mice dramatically improves survival following extended and radical lethal hepatectomy. A20 expression in the liver limits hepatocellular damage hence maintains bilirubin clearance and the liver synthetic function. In addition, A20 confers a proliferative advantage to hepatocytes via decreased expression of the cyclin-dependent kinase inhibitor p21(waf1). In conclusion, A20 provides a proliferative advantage to hepatocytes. By combining anti-inflammatory, antiapoptotic and pro-proliferative functions, A20-based therapies could be beneficial in prevention and treatment of FHF.
Longo
Christopher R
CR
Immunobiology Research Center, Division of Vascular Surgery, and the Transplant Center, Department of Surgery, Harvard Medical School, Boston, MA 02215, USA.
Patel
Virendra I
VI
Shrikhande
Gautam V
GV
Scali
Salvatore T
ST
Csizmadia
Eva
E
Daniel
Soizic
S
Sun
David W
DW
Grey
Shane T
ST
Arvelo
Maria B
MB
Ferran
Christiane
C
D000818:Animals; D018797:Cell Cycle Proteins / Q000502:physiology; D049109:Cell Proliferation; D050759:Cyclin-Dependent Kinase Inhibitor p21; D003546:Cysteine Endopeptidases; D006498:Hepatectomy / Q000009:adverse effects*; D022781:Hepatocytes / Q000502:physiology; D047908:Intracellular Signaling Peptides and Proteins; D008099:Liver / Q000502:physiology; D017093:Liver Failure / Q000209:etiology / Q000235:genetics*; D008115:Liver Regeneration / Q000235:genetics*; D051379:Mice; D023421:Models, Animal; D009687:Nuclear Proteins; D011506:Proteins / Q000235:genetics*; D020127:Recovery of Function; D012038:Regeneration / Q000502:physiology; D016019:Survival Analysis; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3; D016335:Zinc Fingers / Q000235:genetics*
C493957:Cdkn1a protein, mouse; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D047908:Intracellular Signaling Peptides and Proteins; D009687:Nuclear Proteins; D011506:Proteins; D000072598:Tumor Necrosis Factor alpha-Induced Protein 3; D003546:Cysteine Endopeptidases; C513261:Tnfaip3 protein, mouse