Genomes and Genes
Improved liver function and regeneration with A20
Principal Investigator: Christiane Ferran
Affiliation: Harvard University
Abstract: DESCRIPTION (provided by applicant): 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.
Funding Period: ----------------2003 - ---------------2014-
more information: NIH RePORT
- A20, a modulator of smooth muscle cell proliferation and apoptosis, prevents and induces regression of neointimal hyperplasiaVirendra I Patel
The Immunobiology Research Center, Harvard Medical School, Boston Massachusetts, USA
FASEB J 20:1418-30. 2006..If SMC evade this first barrier and neointima is formed, A20 has a therapeutic potential by uniquely sensitizing neointimal SMC to apoptosis. A20-based therapies hold promise for the prevention and treatment of neointimal disease...
- A20 promotes liver regeneration by decreasing SOCS3 expression to enhance IL-6/STAT3 proliferative signalsCleide G da Silva
Division of Vascular and Endovascular Surgery, Center for Vascular Biology Research and the Transplant Institute, Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
Hepatology 57:2014-25. 2013..Upstream of SOCS3, levels of its microRNA regulator miR203 were significantly decreased in A20-deficient livers...
- Endothelial cells are susceptible to rapid siRNA transfection and gene silencing ex vivoNicholas D Andersen
Department of Vascular Surgery Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA
J Vasc Surg 52:1608-15. 2010..Here, we demonstrate endothelial gene silencing in human saphenous vein using three rapid siRNA transfection techniques amenable for use in the operating room...
- Endothelium-dependent coronary vasodilatation requires NADPH oxidase-derived reactive oxygen speciesJun Feng
Department of Surgery, Beth Israel Deaconess Medical Center, Boston, Mass, USA
Arterioscler Thromb Vasc Biol 30:1703-10. 2010..To determine the functional significance of physiological reactive oxygen species (ROS) levels in endothelium-dependent nitric oxide (NO)-mediated coronary vasodilatation...
- The C-terminal domain of A1/Bfl-1 regulates its anti-inflammatory function in human endothelial cellsRenata P Guedes
Department of Surgery, Harvard Medical School, Boston, MA 02215, USA
Biochim Biophys Acta 1833:1553-61. 2013....
- The universal NF-kappaB inhibitor a20 protects from transplant vasculopathy by differentially affecting apoptosis in endothelial and smooth muscle cellsS Daniel
Departments of Surgery and Medicine, Beth Israel Deaconess Medical Centre Harvard Medical School, Boston, Massachusetts 022152, USA
Transplant Proc 38:3225-7. 2006..We propose that A20-based therapies may be effective in prevention and treatment of TV...
- A20-mediated modulation of inflammatory and immune responses in aortic allografts and development of transplant arteriosclerosisJeffrey J Siracuse
Division of Vascular and Endovascular Surgery, Center for Vascular Biology Research and the Transplant Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA
Transplantation 93:373-82. 2012..We have shown that the NF-κB inhibitory protein A20 exerts vasculoprotective effects in endothelial and smooth muscle cells (SMC), and hence is a candidate to prevent TA. We sought direct proof for this hypothesis...
- Hepatocyte growth factor preferentially activates the anti-inflammatory arm of NF-κB signaling to induce A20 and protect renal proximal tubular epithelial cells from inflammationCleide G da Silva
The Division of Vascular Surgery, Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA
J Cell Physiol 227:1382-90. 2012..This could be highly desirable in acute and chronic renal injury where A20-based anti-inflammatory therapies are beneficial...
- A20 modulates lipid metabolism and energy production to promote liver regenerationScott M Damrauer
Division of Vascular Surgery, and the Transplant Institute, Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, United States of America
PLoS ONE 6:e17715. 2011..In this study, we explored the Systems Biology modulated by A20 following extended LR in mice...
- O-glycosylation regulates ubiquitination and degradation of the anti-inflammatory protein A20 to accelerate atherosclerosis in diabetic ApoE-null miceGautam V Shrikhande
The Division of Vascular Surgery, Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, United States of America
PLoS ONE 5:e14240. 2010..Hyperglycemia is a recognized independent risk factor for heightened atherogenesis in diabetes mellitus (DM). However, our understanding of the mechanisms underlying glucose damage to the vasculature remains incomplete...
- TNFalpha-induced macrophage death via caspase-dependent and independent pathwaysTri M Tran
Division of Rheumatology, Department of Medicine, Northwestern University Feinberg School of Medicine, 240 E Huron Street, Chicago, IL 60611, USA
Apoptosis 14:320-32. 2009..These observations demonstrate that TNFalpha triggers both caspase 8-dependent and -independent cell death pathways in macrophages and identify a novel mechanism by which A20 protects these cells against both pathways...
- Mechanism of purinergic activation of endothelial nitric oxide synthase in endothelial cellsCleide Gonçalves da Silva
Center for Vascular Biology Research and the Division of Vascular Surgery, Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA
Circulation 119:871-9. 2009..Extracellular nucleotides activate eNOS and increase NO generation; however, the mechanism of this observation is not fully clarified...
- A20 inhibits post-angioplasty restenosis by blocking macrophage trafficking and decreasing adventitial neovascularizationScott M Damrauer
The Division of Vascular Surgery, Department of Surgery and Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA
Atherosclerosis 211:404-8. 2010....
- A20 protects mice from lethal liver ischemia/reperfusion injury by increasing peroxisome proliferator-activated receptor-alpha expressionHaley E Ramsey
Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
Liver Transpl 15:1613-21. 2009..Liver Transpl 15:1613-1621, 2009. (c) 2009 AASLD...
- Detection of apoptosis in tissue sectionsEva Csizmadia
Center for Vascular Biology, Beth Israel Deaconess Medical Center, Boston, MA, USA
Methods Mol Biol 559:49-63. 2009..The protocol suggested here facilitates not only the reliable detection of TUNEL-positive cells but the immunodetection of different proteins in these cells and the surrounding tissues by DAB or fluorescence-based immunostaining...