Immune-Responsive Gene 1/Itaconate Activates Nuclear Factor Erythroid 2-Related Factor 2 in Hepatocytes to Protect Against Liver Ischemia-Reperfusion Injury.
Animals
Anti-Inflammatory Agents
/ pharmacology
Carboxy-Lyases
/ physiology
Hepatocytes
/ metabolism
Humans
Hydro-Lyases
/ physiology
Liver
/ blood supply
Male
Mice
Mice, Inbred C57BL
NF-E2-Related Factor 2
/ physiology
Oxidative Stress
Reperfusion Injury
/ prevention & control
Signal Transduction
/ physiology
Succinates
/ pharmacology
Journal
Hepatology (Baltimore, Md.)
ISSN: 1527-3350
Titre abrégé: Hepatology
Pays: United States
ID NLM: 8302946
Informations de publication
Date de publication:
10 2020
10 2020
Historique:
received:
07
06
2019
accepted:
23
12
2019
pubmed:
31
1
2020
medline:
4
5
2021
entrez:
31
1
2020
Statut:
ppublish
Résumé
Itaconate, a metabolite of the tricarboxylic acid cycle, plays anti-inflammatory roles in macrophages during endotoxemia. The mechanisms underlying its anti-inflammatory roles have been shown to be mediated by the modulation of oxidative stress, an important mechanism of hepatic ischemia-reperfusion (I/R) injury. However, the role of itaconate in liver I/R injury is unknown. We found that deletion of immune-responsive gene 1 (IRG1), encoding for the enzyme producing itaconate, exacerbated liver injury and systemic inflammation. Furthermore, bone marrow adoptive transfer experiments indicated that deletion of IRG1 in both hematopoietic and nonhematopoietic compartments contributes to the protection mediated by IRG1 after I/R. Interestingly, the expression of IRG1 was up-regulated in hepatocytes after I/R and hypoxia/reoxygenation-induced oxidative stress. Modulation of the IRG1 expression levels in hepatocytes regulated hepatocyte cell death. Importantly, addition of 4-octyl itaconate significantly improved liver injury and hepatocyte cell death after I/R. Furthermore, our data indicated that nuclear factor erythroid 2-related factor 2 (Nrf2) is required for the protective effect of IRG1 on mouse and human hepatocytes against oxidative stress-induced injury. Our studies document the important role of IRG1 in the acute setting of sterile injury induced by I/R. Specifically, we provide evidence that the IRG1/itaconate pathway activates Nrf2-mediated antioxidative response in hepatocytes to protect liver from I/R injury. Our data expand on the importance of IRG1/itaconate in nonimmune cells and identify itaconate as a potential therapeutic strategy for this unfavorable postsurgical complication.
Sections du résumé
BACKGROUND AND AIMS
Itaconate, a metabolite of the tricarboxylic acid cycle, plays anti-inflammatory roles in macrophages during endotoxemia. The mechanisms underlying its anti-inflammatory roles have been shown to be mediated by the modulation of oxidative stress, an important mechanism of hepatic ischemia-reperfusion (I/R) injury. However, the role of itaconate in liver I/R injury is unknown.
APPROACH AND RESULTS
We found that deletion of immune-responsive gene 1 (IRG1), encoding for the enzyme producing itaconate, exacerbated liver injury and systemic inflammation. Furthermore, bone marrow adoptive transfer experiments indicated that deletion of IRG1 in both hematopoietic and nonhematopoietic compartments contributes to the protection mediated by IRG1 after I/R. Interestingly, the expression of IRG1 was up-regulated in hepatocytes after I/R and hypoxia/reoxygenation-induced oxidative stress. Modulation of the IRG1 expression levels in hepatocytes regulated hepatocyte cell death. Importantly, addition of 4-octyl itaconate significantly improved liver injury and hepatocyte cell death after I/R. Furthermore, our data indicated that nuclear factor erythroid 2-related factor 2 (Nrf2) is required for the protective effect of IRG1 on mouse and human hepatocytes against oxidative stress-induced injury. Our studies document the important role of IRG1 in the acute setting of sterile injury induced by I/R. Specifically, we provide evidence that the IRG1/itaconate pathway activates Nrf2-mediated antioxidative response in hepatocytes to protect liver from I/R injury.
CONCLUSIONS
Our data expand on the importance of IRG1/itaconate in nonimmune cells and identify itaconate as a potential therapeutic strategy for this unfavorable postsurgical complication.
Identifiants
pubmed: 31997373
doi: 10.1002/hep.31147
pmc: PMC7702080
doi:
Substances chimiques
Anti-Inflammatory Agents
0
NF-E2-Related Factor 2
0
Succinates
0
ACOD1 protein, human
EC 4.1.1.-
Carboxy-Lyases
EC 4.1.1.-
Hydro-Lyases
EC 4.2.1.-
Irg1 protein, mouse
EC 4.2.1.79
itaconic acid
Q4516562YH
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
1394-1411Subventions
Organisme : NIDDK NIH HHS
ID : P30 DK120531
Pays : United States
Organisme : NIGMS NIH HHS
ID : R01 GM102146
Pays : United States
Informations de copyright
© 2020 The Authors. Hepatology published by Wiley Periodicals, Inc., on behalf of American Association for the Study of Liver Diseases.
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