Ischemia/Reperfusion Injury of Fatty Liver Is Protected by A2AR and Exacerbated by A1R Stimulation through Opposite Effects on ASK1 Activation

Hepatic ischemia/reperfusion injury (IRI) is aggravated by steatosis and is a main risk factor in fatty liver transplantation. Adenosine receptors (ARs) are emerging as therapeutic targets in liver diseases. By using cellular and in vivo systems of hepatic steatosis and IRI, here we evaluated the ef...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Elisa Alchera, Bangalore R. Chandrashekar, Nausicaa Clemente, Ester Borroni, Renzo Boldorini, Rita Carini
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	steatosis ischemia/reperfusion injury hepatic damage oxidative stress adenosine receptor hepatocyte death Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/32c3e3d1bb7b4b1e8ee659da66e56c9b
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:32c3e3d1bb7b4b1e8ee659da66e56c9b
record_format	dspace
spelling	oai:doaj.org-article:32c3e3d1bb7b4b1e8ee659da66e56c9b2021-11-25T17:12:19ZIschemia/Reperfusion Injury of Fatty Liver Is Protected by A2AR and Exacerbated by A1R Stimulation through Opposite Effects on ASK1 Activation10.3390/cells101131712073-4409https://doaj.org/article/32c3e3d1bb7b4b1e8ee659da66e56c9b2021-11-01T00:00:00Zhttps://www.mdpi.com/2073-4409/10/11/3171https://doaj.org/toc/2073-4409Hepatic ischemia/reperfusion injury (IRI) is aggravated by steatosis and is a main risk factor in fatty liver transplantation. Adenosine receptors (ARs) are emerging as therapeutic targets in liver diseases. By using cellular and in vivo systems of hepatic steatosis and IRI, here we evaluated the effects of pharmacological A2AR and A1R activation. The A2AR agonist CGS21680 protected the primary steatotic murine hepatocyte from IR damage and the activation of ASK1 and JNK. Such an effect was attributed to a phosphatidylinositol-3-kinase (PI3K)/Akt-dependent inhibition of ASK1. By contrast, the A1R agonist CCPA enhanced IR damage, intracellular steatosis and oxidative species (OS) production, thereby further increasing the lipid/OS-dependent ASK1-JNK stimulation. The CGS2680 and CCPA effects were nullified by a genetic ASK1 downregulation in steatotic hepatoma C1C7 cells. In steatotic mice livers, CGS21680 protected against hepatic IRI and ASK1/JNK activation whereas CCPA aggravated hepatic steatosis and IRI, and enhanced ASK1 and JNK stimulation. These results evidence a novel mechanism of CGS21680-mediated hepatoprotection, i.e., the PI3K/AKT-dependent inhibition of ASK1, and they show that CGS21680 and CCPA reduces and enhances the IRI of fatty liver, respectively, by preventing or increasing the activation of the cytotoxic ASK1/JNK axis. They also indicate the selective employment of A2AR agonists as an effective therapeutic strategy to prevent IRI in human fatty liver surgery.Elisa AlcheraBangalore R. ChandrashekarNausicaa ClementeEster BorroniRenzo BoldoriniRita CariniMDPI AGarticlesteatosisischemia/reperfusion injuryhepatic damageoxidative stressadenosine receptorhepatocyte deathBiology (General)QH301-705.5ENCells, Vol 10, Iss 3171, p 3171 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	steatosis ischemia/reperfusion injury hepatic damage oxidative stress adenosine receptor hepatocyte death Biology (General) QH301-705.5
spellingShingle	steatosis ischemia/reperfusion injury hepatic damage oxidative stress adenosine receptor hepatocyte death Biology (General) QH301-705.5 Elisa Alchera Bangalore R. Chandrashekar Nausicaa Clemente Ester Borroni Renzo Boldorini Rita Carini Ischemia/Reperfusion Injury of Fatty Liver Is Protected by A2AR and Exacerbated by A1R Stimulation through Opposite Effects on ASK1 Activation
description	Hepatic ischemia/reperfusion injury (IRI) is aggravated by steatosis and is a main risk factor in fatty liver transplantation. Adenosine receptors (ARs) are emerging as therapeutic targets in liver diseases. By using cellular and in vivo systems of hepatic steatosis and IRI, here we evaluated the effects of pharmacological A2AR and A1R activation. The A2AR agonist CGS21680 protected the primary steatotic murine hepatocyte from IR damage and the activation of ASK1 and JNK. Such an effect was attributed to a phosphatidylinositol-3-kinase (PI3K)/Akt-dependent inhibition of ASK1. By contrast, the A1R agonist CCPA enhanced IR damage, intracellular steatosis and oxidative species (OS) production, thereby further increasing the lipid/OS-dependent ASK1-JNK stimulation. The CGS2680 and CCPA effects were nullified by a genetic ASK1 downregulation in steatotic hepatoma C1C7 cells. In steatotic mice livers, CGS21680 protected against hepatic IRI and ASK1/JNK activation whereas CCPA aggravated hepatic steatosis and IRI, and enhanced ASK1 and JNK stimulation. These results evidence a novel mechanism of CGS21680-mediated hepatoprotection, i.e., the PI3K/AKT-dependent inhibition of ASK1, and they show that CGS21680 and CCPA reduces and enhances the IRI of fatty liver, respectively, by preventing or increasing the activation of the cytotoxic ASK1/JNK axis. They also indicate the selective employment of A2AR agonists as an effective therapeutic strategy to prevent IRI in human fatty liver surgery.
format	article
author	Elisa Alchera Bangalore R. Chandrashekar Nausicaa Clemente Ester Borroni Renzo Boldorini Rita Carini
author_facet	Elisa Alchera Bangalore R. Chandrashekar Nausicaa Clemente Ester Borroni Renzo Boldorini Rita Carini
author_sort	Elisa Alchera
title	Ischemia/Reperfusion Injury of Fatty Liver Is Protected by A2AR and Exacerbated by A1R Stimulation through Opposite Effects on ASK1 Activation
title_short	Ischemia/Reperfusion Injury of Fatty Liver Is Protected by A2AR and Exacerbated by A1R Stimulation through Opposite Effects on ASK1 Activation
title_full	Ischemia/Reperfusion Injury of Fatty Liver Is Protected by A2AR and Exacerbated by A1R Stimulation through Opposite Effects on ASK1 Activation
title_fullStr	Ischemia/Reperfusion Injury of Fatty Liver Is Protected by A2AR and Exacerbated by A1R Stimulation through Opposite Effects on ASK1 Activation
title_full_unstemmed	Ischemia/Reperfusion Injury of Fatty Liver Is Protected by A2AR and Exacerbated by A1R Stimulation through Opposite Effects on ASK1 Activation
title_sort	ischemia/reperfusion injury of fatty liver is protected by a2ar and exacerbated by a1r stimulation through opposite effects on ask1 activation
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/32c3e3d1bb7b4b1e8ee659da66e56c9b
work_keys_str_mv	AT elisaalchera ischemiareperfusioninjuryoffattyliverisprotectedbya2arandexacerbatedbya1rstimulationthroughoppositeeffectsonask1activation AT bangalorerchandrashekar ischemiareperfusioninjuryoffattyliverisprotectedbya2arandexacerbatedbya1rstimulationthroughoppositeeffectsonask1activation AT nausicaaclemente ischemiareperfusioninjuryoffattyliverisprotectedbya2arandexacerbatedbya1rstimulationthroughoppositeeffectsonask1activation AT esterborroni ischemiareperfusioninjuryoffattyliverisprotectedbya2arandexacerbatedbya1rstimulationthroughoppositeeffectsonask1activation AT renzoboldorini ischemiareperfusioninjuryoffattyliverisprotectedbya2arandexacerbatedbya1rstimulationthroughoppositeeffectsonask1activation AT ritacarini ischemiareperfusioninjuryoffattyliverisprotectedbya2arandexacerbatedbya1rstimulationthroughoppositeeffectsonask1activation
_version_	1718412639870124032

Ischemia/Reperfusion Injury of Fatty Liver Is Protected by A2AR and Exacerbated by A1R Stimulation through Opposite Effects on ASK1 Activation

Ejemplares similares