TY - JOUR
T1 - Heme oxygenase-1 regulates sirtuin-1–autophagy pathway in liver transplantation
T2 - From mouse to human
AU - Nakamura, Kojiro
AU - Kageyama, Shoichi
AU - Yue, Shi
AU - Huang, Jing
AU - Fujii, Takehiro
AU - Ke, Bibo
AU - Sosa, Rebecca A.
AU - Reed, Elaine F.
AU - Datta, Nakul
AU - Zarrinpar, Ali
AU - Busuttil, Ronald W.
AU - Kupiec-Weglinski, Jerzy W.
N1 - Funding Information:
This work was supported by National Institutes of Health (NIH) grants R01 DK102110; R01 DK107533; and R01 DK062357 (JWKW); NIH PO1 AI120944 and Keck Foundation Award 986722 (JWKW and EFR); and Ruth L. Kirschstein National Research Service Award T32CA009120 (RAS). The authors declare that no conflicts of interest exist. We thank Ko Takanashi at UCLA-TPCL for immunohistochemi-
Publisher Copyright:
© 2017 The American Society of Transplantation and the American Society of Transplant Surgeons
PY - 2018/5
Y1 - 2018/5
N2 - Liver ischemia–reperfusion injury (IRI) represents a major risk factor of early graft dysfunction and a key obstacle to expanding the donor pool in orthotopic liver transplantation (OLT). Although graft autophagy is essential for resistance against hepatic IRI, its significance in clinical OLT remains unknown. Despite recent data identifying heme oxygenase-1 (HO-1) as a putative autophagy inducer, its role in OLT and interactions with sirtuin-1 (SIRT1), a key autophagy regulator, have not been studied. We aimed to examine HO-1–mediated autophagy induction in human OLT and in a murine OLT model with extended (20 hours) cold storage, as well as to analyze the requirement for SIRT1 in autophagy regulation by HO-1. Fifty-one hepatic biopsy specimens from OLT patients were collected under an institutional review board protocol 2 hours after portal reperfusion, followed by Western blot analyses. High HO-1 levels correlated with well-preserved hepatocellular function and enhanced SIRT1/LC3B expression. In mice, HO-1 overexpression by genetically modified HO-1 macrophage therapy was accompanied by decreased OLT damage and increased SIRT1/LC3B expression, whereas adjunctive inhibition of SIRT1 signaling diminished HO-1–mediated hepatoprotection and autophagy induction. Our translational study confirms the clinical relevance of HO-1 cytoprotection and identifies SIRT1-mediated autophagy pathway as a new essential regulator of HO-1 function in IR-stressed OLT.
AB - Liver ischemia–reperfusion injury (IRI) represents a major risk factor of early graft dysfunction and a key obstacle to expanding the donor pool in orthotopic liver transplantation (OLT). Although graft autophagy is essential for resistance against hepatic IRI, its significance in clinical OLT remains unknown. Despite recent data identifying heme oxygenase-1 (HO-1) as a putative autophagy inducer, its role in OLT and interactions with sirtuin-1 (SIRT1), a key autophagy regulator, have not been studied. We aimed to examine HO-1–mediated autophagy induction in human OLT and in a murine OLT model with extended (20 hours) cold storage, as well as to analyze the requirement for SIRT1 in autophagy regulation by HO-1. Fifty-one hepatic biopsy specimens from OLT patients were collected under an institutional review board protocol 2 hours after portal reperfusion, followed by Western blot analyses. High HO-1 levels correlated with well-preserved hepatocellular function and enhanced SIRT1/LC3B expression. In mice, HO-1 overexpression by genetically modified HO-1 macrophage therapy was accompanied by decreased OLT damage and increased SIRT1/LC3B expression, whereas adjunctive inhibition of SIRT1 signaling diminished HO-1–mediated hepatoprotection and autophagy induction. Our translational study confirms the clinical relevance of HO-1 cytoprotection and identifies SIRT1-mediated autophagy pathway as a new essential regulator of HO-1 function in IR-stressed OLT.
KW - basic (laboratory) research/science
KW - biopsy
KW - immunobiology
KW - liver disease: immune/inflammatory
KW - liver transplantation/hepatology
KW - organ perfusion and preservation
KW - tissue injury and repair
KW - translational research/science
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U2 - 10.1111/ajt.14586
DO - 10.1111/ajt.14586
M3 - Article
C2 - 29136322
AN - SCOPUS:85038095668
VL - 18
SP - 1110
EP - 1121
JO - American Journal of Transplantation
JF - American Journal of Transplantation
SN - 1600-6135
IS - 5
ER -