Sirtuin-1 expression and activity is diminished in aged liver grafts

Abstract

The cellular mechanisms underlying impaired function of aged liver grafts have not been fully elucidated, but mitochondrial dysfunction appears to be contributory. Sirtuin1 has been identified as a key mediator of mitochondrial recovery following ischemia-reperfusion injury. The purpose of this study was to determine whether differences exist in sirtuin-1 expression/activity in old vs. young liver grafts and to determine correlations with mitochondrial function, graft metabolic function, and graft injury. Old and young rat liver grafts (N = 7 per group) were exposed to 12 h of static cold storage (SCS), followed by a 2 h period of graft reperfusion ex vivo. Sirtuin1 expression and activity, mitochondrial function, graft metabolic function, and graft injury were compared. Sirtuin1 expression is upregulated in young, but not old, liver grafts in response to cold storage and reperfusion. This is associated with diminished tissue ATP, antioxidant defense, and graft metabolic function in old liver grafts. There was no evidence of increased inflammation or histologic injury in old grafts. Sirtuin1 expression is diminished in old liver grafts and correlates with mitochondrial and metabolic function. The sirtuin pathway may represent a target for intervention to enhance the function of aged liver grafts. Abbreviations ACI August Copenhagen Irish ECD Extended criteria donor; exDNA Extracellular DNA HEK Human embryonic kidney HMGB1 High-mobility group box 1 I-R Ischemia-reperfusion LDH Lactate dehydrogenase LT Liver transplantation PGC1α Peroxisome proliferator-activated receptor gamma coactivator 1-alpha SCS Static cold storage SEAP Secreted embryonic alkaline phosphatase SOD Superoxide dismutase TLR Toll-like receptor TNF Tumor necrosis factor Although liver transplant (LT) outcomes are excellent in the modern era, the field continues to be limited by a shortage of suitable donor organs. Recent efforts have focused on expanding the donor pool by utilizing grafts from extended criteria donors (ECDs), including donors of advanced age 1. Although LT outcomes using older grafts have improved over time 2,3 , multiple studies have identified advanced donor age as an independent risk factor in impaired graft outcomes 4-6. These inferior clinical outcomes have been attributed to a reduced capacity of older grafts to recover from prolonged cold ischemia and ischemia-reperfusion (I-R) injury 7-10. From a cellular perspective, mitochondrial dysfunction has been recognized as a central mediator of liver I-R injury, characterized by ATP depletion, reactive oxygen species (ROS) generation, and cell death 11-13. Recent studies have demonstrated the importance of sirtuin-1, an NAD +-dependent deacetylase, in mitochondrial recovery pathways following I-R injury of the liver 14-16. These effects are attributed to the role played by

Up‐regulated LRRN2 expression as a marker for graft quality in living donor liver transplantation

“…Furthermore, SIRT1 expression was diminished, which also has been reported in rodent model aged liver grafts. [ 27 ] Collectively, these findings confirmed the suitability of cynomolgus macaques as an aging model for research regarding liver transplantation.…”

“…Genes involving senescence‐associated secretory phenotype (SASP) and cyclin‐dependent kinase inhibitor 1A (CDKN2A; p16) were up‐regulated in the elderly, while sirtuins ( SIRT ) were down‐regulated, as also observed in human studies for SASP, [ 25 ] p16, [ 26 ] and SIRT . [ 27 ] Moreover, it is well known that liver fibrogenesis triggered by chronic damage is increased in the elderly. [ 28 ] Genes involved in liver fibrogenesis, such as interleukin (IL)‐34, are also up‐regulated in the elderly macaques, as reported in advanced liver cirrhosis.…”

[Retracted] Fluoride Exposure Suppresses Proliferation and Enhances Endoplasmic Reticulum Stress and Apoptosis Pathways in Hepatocytes by Downregulating Sirtuin‐1

“…Besides, Sirt-1 has been reported to play key regulatory roles in physiological processes such as apoptosis, differentiation, oxidative stress, senescence, signaling, transcriptional regulation, and metabolic regulation through the regulation of histones, NF- κ B, FOXO, and p53 [ 53 , 54 ]. In recent years, studies confirmed that Sirt-1 is essential in liver-related diseases, such as liver transplantation [ 55 ], liver ischemia/reperfusion injury [ 56 ], liver fibrosis [ 57 ], fatty liver [ 58 ], alcoholic liver injury, and fibrosis [ 59 ]. At the same time, the role and mechanism of Sirt-1 in liver injury induced by fluoride exposure are unclear.…”

The role of the tryptophan-NAD + pathway in a mouse model of severe malnutrition induced liver dysfunction

“…SIRT1 activity was quantified with a SIRT1 Activity Fluorometric Assay Kit (Abcam, USA) following the manufacturer's instructions 93 . Protein concentrations were determined using a Pierce BCA Protein Assay Kit (Thermo Fisher Scientific, USA).…”