ADP and P2Y13 receptor are involved in the autophagic protection of ex vivo perfused livers from fasted rats: Potential benefit for liver graft preservation.
AMPK; HMGB1; cell signalling; liver cytolysis enzyme markers; organ protection and diet restriction
Abstract :
[en] Studies on how to protect livers perfused ex vivo can help design strategies for hepatoprotection and liver graft preservation. Protection of livers isolated from 24- vs. 18-h-starved rats has been previously attributed to autophagy, which contributes to the energy-mobilizing capacity ex vivo. Here, we explored the signaling pathways responsible for this protection. In our experimental models, three major signaling candidates were considered in view of their abilities to trigger autophagy: HMGB1, AMPK, and purinergic receptor P2Y13. To this end, ex vivo livers isolated from starved rats were perfused for 135 min, after which perfusate samples were studied for protein release and biopsies were performed for evaluating signaling protein contents. For HMGB1, no significant difference was observed between livers isolated from rats starved for 18 and 24 h at perfusion times of both 0 and 135 min. The phosphorylated and total forms of AMPK, but not their ratio, were significantly higher in 24-h-fasted than in 18-h-fasted livers. However, although the level of phosphorylated AMPK increased, perfusing ex vivo 18-h-fasted livers with 1 mM AICAR, an AMPK activator, did not protect the livers. Additionally, ADP (and not AMP) to AMP+ADP+ATP ratio increased in 24-h-starved livers compared to that in 18-h-starved livers. Moreover, perfusing 24-h-starved livers with 0.1 mM MRS2211, a specific antagonist of P2Y13 receptor, induced an increase in cytolysis marker levels in the perfusate samples and a decrease in the levels of autophagic marker LC3II/actin (and loss of p62/actin decrease), indicating autophagy inhibition and loss of protection. Conclusion: The P2Y13 receptor and ADP (a physiological activator of this receptor) are involved in the protection of ex vivo livers. Therapeutic opportunities for improving liver graft preservation through the stimulation of the ADP-P2Y13 receptor axis are further discussed.
Albert, Adelin ; Université de Liège - ULiège > Département des sciences de la santé publique > Département des sciences de la santé publique
Cherkaoui-Malki, Mustapha
Andreoletti, Pierre
Leo, Oberdan
Kruys, Véronique; Université Libre de Bruxelles - ULB
Boogaerts, Jean G.; CHU Charleroi > Anesthésiologie
Vamecq, Joseph; INSERM
Language :
English
Title :
ADP and P2Y13 receptor are involved in the autophagic protection of ex vivo perfused livers from fasted rats: Potential benefit for liver graft preservation.
Publication date :
2020
Journal title :
Liver Transplantation
ISSN :
1527-6465
eISSN :
1527-6473
Peer reviewed :
Peer Reviewed verified by ORBi
Commentary :
This article is protected by copyright. All rights reserved.
Testa G, Biasi F, Poli G, Chiarpotto E. Calorie restriction and dietary restriction mimetics: a strategy for improving healthy aging and longevity. Curr Pharm Des 2014;20:2950-2977.
Rickenbacher A, Jang JH, Limani P, Ungethüm U, Lehmann K, Oberkofler CE, et al. Fasting protects liver from ischemic injury through Sirt1-mediated downregulation of circulating HMGB1 in mice. J Hepatol 2014;61:301-308.
Papegay B, Stadler M, Nuyens V, Kruys V, Boogaerts JG, Vamecq J. Short fasting does not protect perfused ex vivo rat liver against ischemia-reperfusion. On the importance of a minimal cell energy charge. Nutrition 2017;35:21-27.
Papegay B, Nuyens V, Albert A, Cherkaoui-Malki M, Leo O, Kruys V, et al. Protection in a model of liver injury is parallel to energy mobilization capacity under distinct nutritional status. Nutrition 2019;67-68:110517.
Stadler M, Nuyens V, Boogaerts JG. Intralipid minimizes hepatocytes injury after anoxia-reoxygenation in an ex vivo rat liver model. Nutrition 2007;23:53-61.
Papegay B, Stadler M, Nuyens V, Salmon I, Kruys V, Boogaerts JG. Alanine minimizes hepatocyte injury after ischemia-reperfusion in an ex vivo rat liver model. Biocell 2014;38:25-32.
Papegay B, Nuyens V, Kruys V, Boogaerts JG, Vamecq J. L-Lactate-based improvement of energetic charge and protection of rat liver. Liver Transpl 2019;25:1571-1575.
Heras-Sandoval D, Pérez-Rojas JM, Hernández-Damián J, Pedraza-Chaverri J. The role of PI3K/AKT/mTOR pathway in the modulation of autophagy and the clearance of protein aggregates in neurodegeneration. Cell Signal 2014;26:2694-2701.
Alers S, Löffler AS, Wesselborg S, Stork B. Role of AMPK-mTOR-Ulk1/2 in the regulation of autophagy: cross talk, shortcuts, and feedbacks. Mol Cell Biol 2012;32:2-11.
Tang D, Kang R, Livesey KM, Cheh CW, Farkas A, Loughran P, et al. Endogenous HMGB1 regulates autophagy. J Cell Biol 2010;190:881-892.
Chatterjee C, Sparks DL. Hepatic lipase release is inhibited by a purinergic induction of autophagy. Cell Physiol Biochem 2014;33:883-894.
Kim J, Yang G, Kim Y, Kim J, Ha J. AMPK activators: mechanisms of action and physiological activities. Exp Mol Med 2016;48:e224.
Herzig S, Shaw RJ. AMPK: guardian of metabolism and mitochondrial homeostasis. Nat Rev Mol Cell Biol 2018;19:121-135.
Jacobson KA, Delicado EG, Gachet C, Kennedy C, von Kügelgen I, Li B, et al. Update of P2Y receptor pharmacology: IUPHAR review 27. Br J Pharmacol 2020;177:2413-2433.
Xiao B, Sanders MJ, Underwood E, Health R, Mayer FV, Carmena D, et al. Structure of mammalian AMPK and its regulation by ADP. Nature 2011;472:230-233.
Coccimiglio IF, Clarke DC. ADP is the dominant controller of AMP-activated protein kinase activity dynamics in skeletal muscle during exercise. PLoS Comput Biol 2020;16:e1008079.
Chatterjee C, Sparks DL. Extracellular nucleotides inhibit insulin receptor signaling, stimulate autophagy and control lipoprotein secretion. PLoS One 2012;7:e36916.
Fabre AC, Vantourout P, Champagne E, Tercé F, Rolland C, Perret B, et al. Cell surface adenylate kinase activity regulates the F(1)-ATPase/P2Y (13)-mediated HDL endocytosis pathway on human hepatocytes. Cell Mol Life Sci 2006;63:2829-2837.
Jeffrey JL, Lawson KV, Powers JP. Targeting metabolism of extracellular nucleotides via inhibition of ectonucleotidases CD73 and CD39. J Med Chem 2020;63:13444-13465.
Wang S, Gao S, Zhou D, Qian X, Luan J, Lv X. The role of the CD39-CD73-adenosine pathway in liver disease. J Cell Physiol 2021;236:851-862.
Goffinet M, Tardy C, Boubekeur N, Cholez G, Bluteau A, Oniciu DC, et al. P2Y13 receptor regulates HDL metabolism and atherosclerosis in vivo. PLoS One 2014;9:e95807.
Jacquet S, Malaval C, Martinez LO, Sak K, Rolland C, Perez C, et al. The nucleotide receptor P2Y13 is a key regulator of hepatic high-density lipoprotein (HDL) endocytosis. Cell Mol Life Sci 2005;62:2508-2515.
Serhan N, Cabou C, Verdier C, Lichtenstein L, Malet N, Perret B, et al. Chronic pharmacological activation of P2Y13 receptor in mice decreases HDL-cholesterol level by increasing hepatic HDL uptake and bile acid secretion. Biochim Biophys Acta 2013;1831:719-725.
Martinez LO, Cardouat G, Fried S, Najib S. An unexpected role of autophagy in targeting functional mitochondrial ATP synthase to the plasma membrane: its role in HDL endocytosis. Atherosclerosis 2016;252:e258.
Aires CC, van Cruchten A, Ijlst L, de Almeida IT, Duran M, Wanders RJ, et al. New insights on the mechanisms of valproate-induced hyperammonemia: inhibition of hepatic N-acetylglutamate synthase activity by valproyl-CoA. J Hepatol 2011;55:426-434.
Iranshahy M, Rezaee R, Karimi G. Hepatoprotective activity of metformin: a new mission for an old drug? Eur J Pharmacol 2019;850:1-7.
Li M, Sharma A, Yin C, Tan X, Xiao Y. Metformin ameliorates hepatic steatosis and improves the induction of autophagy in HFD-induced obese mice. Mol Med Rep 2017;16:680-686.
Mohsin AA, Chen Q, Quan N, Rousselle T, Maceyka MW, Samidurai A, et al. Mitochondrial complex I inhibition by metformin limits reperfusion injury. J Pharmacol Exp Ther 2019;369:282-290.
Zheng J, Ramirez VD. Inhibition of mitochondrial proton F0F1-ATPase/ATP synthase by polyphenolic phytochemicals. Br J Pharmacol 2000;130:1115-1123.
Tejada S, Capó X, Mascaró CM, Monserrat-Mesquida M, Quetglas-Llabrés MM, Pons A, et al. Hepatoprotective effects of resveratrol in non-alcoholic fatty liver disease. Curr Pharm Des; 2020. https://doi.org/10.2174/1381612826666200417165801.
Pineda-Ramírez N, Alquisiras-Burgos I, Ortiz-Plata A, Ruiz-Tachiquín ME, Espinoza-Rojo M, Aguilera P. Resveratrol activates neuronal autophagy through AMPK in the ischemic brain. Mol Neurobiol 2020;57:1055-1069.
Patel BA, D'Amico TL, Blagg BSJ. Natural products and other inhibitors of F1FO ATP synthase. Eur J Med Chem 2020;207:112779.
Divakaruni AS, Brand MD. The regulation and physiology of mitochondrial proton leak. Physiology (Bethesda) 2011;26:192-205.
Childress ES, Alexopoulos SJ, Hoehn KL, Santos WL. Small molecule mitochondrial uncouplers and their therapeutic potential. J Med Chem 2018;61:4641-4655.
Park JS, Lee YS, Bae SH. Repositioning of niclosamide ethanolamine (NEN), an anthelmintic drug, for the treatment of lipotoxicity. Free Rad Biol Med 2019;137:143-157.
Han P, Shao M, Guo L, Wang W, Song G, Yu X, et al. Niclosamide ethanolamine improves diabetes and diabetic kidney disease in mice. Am J Transl Res 2018;10:1071-1084.
Agius L, Ford BE, Chachra SS. The metformin mechanism on gluconeogenesis and AMPK activation: the metabolite perspective. Int J Mol Sci 2020;21:3240.
Trepiana J, Milton-Laskibar I, Gómez-Zorita S, Eseberri I, González M, Fernández-Quintela A, et al. Involvement of 5'-activated protein kinase (AMPK) in the effects of resveratrol on liver steatosis. Int J Mol Sci 2018;19:3473.
Zhao H, Shu L, Huang W, Song G, Ma H. Resveratrol affects hepatic gluconeogenesis via histone deacetylase 4. Diabetes Metab Syndr Obes 2019;12:401-411.
Martinez LO, Najib S, Perret B, Cabou C, Lichtenstein L. Ecto-F1-ATPase/P2Y pathways in metabolic and vascular functions of high density lipoproteins. Atherosclerosis 2015;238:89-100.
Khodja Y, Samuels ME. Ethanol-mediated upregulation of APOA1 gene expression in HepG2 cells is independent of de novo lipid biosynthesis. Lipids Health Dis 2020;19:144.
Ozaras R, Tahan V, Aydin S, Uzun H, Kaya S, Senturk H. N-acetylcysteine attenuates alcohol-induced oxidative stess in rats. World J Gastroenterol 2003;9:791-794.
Verdier C, Martinez LO, Ferrières J, Elbaz M, Genoux A, Perret B. Targeting high-density lipoproteins: update on a promising therapy. Arch Cardiovasc Dis 2013;106:601-611.
Pedrini S, Chatterjee P, Hone E, Martins RN. High-density lipoprotein-related cholesterol metabolism in Alzheimer's disease. J Neurochem; 2020. https://doi.org/10.1111/jnc.15170.
Joncquel-Chevalier Curt M, Voicu PM, Fontaine M, Dessein AF, Porchet N, Mention-Mulliez K, et al. Creatine biosynthesis and transport in health and disease. Biochimie 2015;119:146-165.
Storey RF, Sinha A. Cangrelor for the management and prevention of arterial thrombosis. Expert Rev Cardiovasc Ther 2016;14:991-999.
Schlattner U, Klaus A, Ramirez Rios S, Guzun R, Kay L, Tokarska-Schlattner M. Cellular compartmentation of energy metabolism: creatine kinase microcompartments and recruitment of B-type creatine kinase to specific subcellular sites. Amino Acids 2016;48:1751-1774.
