脂肪变性肝移植保存中沉默信息调节因子1与高迁移率族蛋白B1之间的相互作用

Cross-Talk Between Sirtuin 1 and High-Mobility Box 1 in Steatotic Liver Graft Preservation.

作者信息

Zaouali M A, Panisello A, Lopez A, Folch E, Castro-Benítez C, Adam R, Roselló-Catafau J

机构信息

Experimental Hepatic Ischemia-Reperfusion Unit, Institut d'Investigacions Biomèdiques de Barcelona (IIBB), CSIC-IDIBAPS, Barcelona, Spain; Research Unit of Biology and Molecular Anthropology Applied to Development and Health (UR12ES11), Faculty of Pharmacy, University of Monastir, Tunisia; High Institut of Biotechnology of Monastir, University of Monastir, Tunisia.

Experimental Hepatic Ischemia-Reperfusion Unit, Institut d'Investigacions Biomèdiques de Barcelona (IIBB), CSIC-IDIBAPS, Barcelona, Spain.

出版信息

Transplant Proc. 2017 May;49(4):765-769. doi: 10.1016/j.transproceed.2017.01.071.

DOI:10.1016/j.transproceed.2017.01.071

PMID:28457391

Abstract

BACKGROUND

Sirtuin 1 (SIRT1) is a nicotinamide adenine dinucleotide +-dependent histone deacetylase that regulates various pathways involved in ischemia-reperfusion injury (IRI). Moreover, high-mobility group box 1 protein (HMGB1) has also been involved in inflammatory processes during IRI. However, the roles of both SIRT1 and HMGB1 in liver preservation is poorly understood. In this communication, we evaluated the potential relationship between SIRT1 and HMGB1 in steatotic and non-steatotic liver grafts preserved in Institute Georges Lopez solution (IGL-1) preservation solution enriched or not enriched with trimetazidine (TMZ).

METHODS

Steatotic and non-steatotic livers were preserved in IGL-1 preservation solution (24 hours, 4°C), enriched or not enriched with TMZ (10 μmol/L), and then submitted to ex vivo reperfusion (2 hours; 37°C). Liver injury (AST/ALT) and function (bile output, vascular resistance) were evaluated. SIRT1, HMGB1, autophagy parameters (beclin-1, LC3B), PPAR-γ, and heat-shock protein (HO-1, HSP70) expression were determined by means of Western blot. Also, we assessed oxidative stress, mitochondrial damage (glutamate dehydrogenase), and TNF-α levels.

RESULTS

Elevated SIRT1 and enhanced autophagy were found after reperfusion in steatotic livers preserved in IGL-1+TMZ when compared with IGL-1. However, these changes were not seen in the case of non-steatotic livers. Also, HO-1 increases in the IGL-1 + TMZ group were evident only in the case of steatotic livers, whereas HSP70 and PPAR-γ protein expression were enhanced only in non-steatotic livers. All reported changes were consistent with decreased liver injury diminution, ameliorated hepatic function, and decreased TNF-α and HMGB levels. In addition, the oxidative stress and mitochondrial damage were efficiently prevented by the IGL-1 + TMZ use.

CONCLUSIONS

SIRT1 is associated with HMGB1 decreases and increased autophagy in steatotic livers, contributing to increased tolerance to cold IRI.

摘要

背景

沉默调节蛋白1（SIRT1）是一种烟酰胺腺嘌呤二核苷酸依赖性组蛋白脱乙酰酶，可调节缺血再灌注损伤（IRI）涉及的各种途径。此外，高迁移率族蛋白B1（HMGB1）也参与了IRI期间的炎症过程。然而，SIRT1和HMGB1在肝脏保存中的作用尚不清楚。在本报告中，我们评估了在添加或未添加曲美他嗪（TMZ）的乔治·洛佩斯研究所溶液（IGL-1）保存液中保存的脂肪变性和非脂肪变性肝移植中SIRT1和HMGB1之间的潜在关系。

方法

将脂肪变性和非脂肪变性肝脏保存在IGL-1保存液（24小时，4°C）中，添加或不添加TMZ（10μmol/L），然后进行体外再灌注（2小时；37°C）。评估肝损伤（AST/ALT）和肝功能（胆汁分泌、血管阻力）。通过蛋白质印迹法测定SIRT1、HMGB1、自噬参数（贝林蛋白-1、LC3B）、过氧化物酶体增殖物激活受体γ（PPAR-γ）和热休克蛋白（血红素加氧酶-1、HSP70）的表达。此外，我们评估了氧化应激、线粒体损伤（谷氨酸脱氢酶）和肿瘤坏死因子-α（TNF-α）水平。

结果

与IGL-1相比，在IGL-1+TMZ中保存的脂肪变性肝脏再灌注后发现SIRT1升高和自噬增强。然而，在非脂肪变性肝脏中未观察到这些变化。此外，IGL-1+TMZ组中血红素加氧酶-1的增加仅在脂肪变性肝脏中明显，而HSP70和PPAR-γ蛋白表达仅在非脂肪变性肝脏中增强。所有报告的变化均与肝损伤减轻、肝功能改善以及TNF-α和HMGB水平降低一致。此外，使用IGL-1+TMZ可有效预防氧化应激和线粒体损伤。