The liver has remarkable regenerative capacity, allowing recovery following injury or resection. Adequate regeneration is, however, contingent upon maintenance of a healthy residual liver mass, otherwise fulminant hepatic failure ensues. This issue is of particular importance in liver transplantation where allografts face substantial ischemic, inflammatory, and immune insults that are further exacerbated in adult living donor liver transplants using "small-for-size" liver grafts. Understanding the physiologic protective mechanisms safeguarding hepatocytes and promoting their proliferation is critical for devising therapeutic strategies aimed at improving outcome of liver transplantation. We have identified the 7-Zinc finger protein A20 as a critical component of the protective and regenerative responses of hepatocytes in that it protects hepatocytes from apoptosis by altering the expression of the initiator Caspase 8;safeguards hepatocytes from ischemic necrosis by limiting oxidative damage;contains hepatocyte inflammatory responses by inhibiting NFkB activation;and promotes hepatocyte proliferation by decreasing the expression of the Cyclin Dependent Kinase Inhibitor p21waf1. These "hepatoprotective" functions of A20 translate into a dramatic regenerative advantage with greatly improved survival following radical lethal hepatectomy or prolonged liver ischemia in mice. Interestingly, transcription of A20 is decreased in "small-for-size" liver grafts, likely contributing to increased damage and inadequate regeneration. We have recently unraveled novel targets for A20 in hepatocytes that may account for its beneficial effects: 1) Increases the expression of Peroxisome Proliferator-Activated Receptor alpha (PPAR1), 2) Decreases the expression of p21waf1 and 3) Enhances Signal Transducer and Activator of Transcription 3 (STAT-3) phosphorylation despite lower IL-6 levels through decreasing Suppressor of Cytokine Signaling (SOCS)-3 expression We wish to:
Specific Aim 1 : Decipher the molecular basis for the A20 dependent protection of hepatocytes from necrotic cell death following oxidative damage and probe the involvement of PPAR1 in mediating this effect.
Specific Aim 2 : Explore the molecular basis for the pro-proliferative function of A20 in hepatocytes by investigating the role of p21waf1 and IL-6/STAT-3/SOCS3 in supporting this effect.
Specific Aim 3 : Evaluate the impact of A20 expression in the liver upon survival and function of non- optimal liver grafts, including small-for-size liver grafts and grafts with prolonged ischemia time. Demonstrating A20's beneficial effects in our experimental models should set the basis for translating A20- based therapies into clinical practice.

Public Health Relevance

Orthotopic liver transplantation is a life-saving measure for patients suffering from acute or chronic liver failure. However, demand exceeds organ availability by several orders of magnitude, causing a number of patients to die while on the waiting list. We have identified the A20 protein as an ideal hepatoprotective candidate. A20 combines anti-apoptotic, anti-necrotic, anti-inflammatory, anti-oxidative and pro-proliferative functions in hepatocytes, which translates into significant survival and regenerative advantages following radical lethal hepatectomy and severe ischemia reperfusion injury in mice. We wish to test the effectiveness of A20-based therapies in improving survival and function of sub-optimal liver grafts that are usually unsuitable for transplantation. Any beneficial effects of A20 in these models would expand the pool of liver donors and help ease the severe organ shortage in liver transplantation.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK063275-10
Application #
8477175
Study Section
Hepatobiliary Pathophysiology Study Section (HBPP)
Program Officer
Serrano, Jose
Project Start
2003-01-01
Project End
2014-05-31
Budget Start
2013-06-01
Budget End
2014-05-31
Support Year
10
Fiscal Year
2013
Total Cost
$349,709
Indirect Cost
$143,998
Name
Beth Israel Deaconess Medical Center
Department
Type
DUNS #
071723621
City
Boston
State
MA
Country
United States
Zip Code
02215
da Silva, Cleide Gonçalves; Cervantes, Jesus Revuelta; Studer, Peter et al. (2014) A20--an omnipotent protein in the liver: prometheus myth resolved? Adv Exp Med Biol 809:117-39
Mele, Alessandra; Cervantes, Jesus Revuelta; Chien, Victor et al. (2014) Single nucleotide polymorphisms at the TNFAIP3/A20 locus and susceptibility/resistance to inflammatory and autoimmune diseases. Adv Exp Med Biol 809:163-83
Guedes, Renata Padilha; Csizmadia, Eva; Moll, Herwig P et al. (2014) A20 deficiency causes spontaneous neuroinflammation in mice. J Neuroinflammation 11:122
McGillicuddy, Fiona C; Moll, Herwig P; Farouk, Samira et al. (2014) Translational studies of A20 in atherosclerosis and cardiovascular disease. Adv Exp Med Biol 809:83-101
da Silva, Cleide Gonçalves; Minussi, Darlan Conterno; Ferran, Christiane et al. (2014) A20 expressing tumors and anticancer drug resistance. Adv Exp Med Biol 809:65-81
da Silva, Cleide G; Studer, Peter; Skroch, Marco et al. (2013) A20 promotes liver regeneration by decreasing SOCS3 expression to enhance IL-6/STAT3 proliferative signals. Hepatology 57:2014-25
Guedes, Renata P; Rocha, Eduardo; Mahiou, Jerome et al. (2013) The C-terminal domain of A1/Bfl-1 regulates its anti-inflammatory function in human endothelial cells. Biochim Biophys Acta 1833:1553-61
Siracuse, Jeffrey J; Fisher, Mark D; da Silva, Cleide G et al. (2012) A20-mediated modulation of inflammatory and immune responses in aortic allografts and development of transplant arteriosclerosis. Transplantation 93:373-82
da Silva, Cleide G; Maccariello, Elizabeth R; Wilson, Szuhuei Wu et al. (2012) Hepatocyte growth factor preferentially activates the anti-inflammatory arm of NF-*B signaling to induce A20 and protect renal proximal tubular epithelial cells from inflammation. J Cell Physiol 227:1382-90
Damrauer, Scott M; Studer, Peter; da Silva, Cleide G et al. (2011) A20 modulates lipid metabolism and energy production to promote liver regeneration. PLoS One 6:e17715

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