Oroxylin a promotes PGC-1α/Mfn2 signaling to attenuate hepatocyte pyroptosis via blocking mitochondrial ROS in alcoholic liver disease.
Animals
Flavonoids
GTP Phosphohydrolases
/ metabolism
Hepatocytes
/ metabolism
Liver Diseases, Alcoholic
/ drug therapy
Male
Mice
Mice, Inbred ICR
Mitochondria
/ metabolism
Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
/ genetics
Pyroptosis
Reactive Oxygen Species
/ metabolism
Alcoholic liver disease
Hepatocyte
Mitofusin 2
Oroxylin A
Proliferator-activated receptor gamma coactivator 1 alpha
Pyroptosis
Journal
Free radical biology & medicine
ISSN: 1873-4596
Titre abrégé: Free Radic Biol Med
Pays: United States
ID NLM: 8709159
Informations de publication
Date de publication:
06 2020
06 2020
Historique:
received:
16
12
2019
revised:
10
03
2020
accepted:
30
03
2020
pubmed:
15
4
2020
medline:
22
6
2021
entrez:
15
4
2020
Statut:
ppublish
Résumé
It is well acknowledged that alcoholic liver disease (ALD) is widely prevalent all over the world, characterized by aberrant lipid deposition and excessive oxidative stress in hepatocytes. Recently, pyroptosis, a new type of programmed cell death, has been found in ALD, which provides new ideas for the treatment of ALD. Male ICR mice were treated with the Lieber-De-Carli diet (Dyets) or isocaloric liquid diet for 8 weeks, and binge alcohol model was also used for ALD. Blood and livers were taken to evaluate the efficacy of oroxylin A. The levels of factors related to hepatocyte pyroptosis were measured via western blot analyses, immunofluorescence analyses and quantitative reverse transcriptase in vitro. Our study found that oroxylin A suppressed hepatocyte pyroptosis through a NLRP3 inflammasome dependent-canonical caspase-1 pathway. Results illuminated that oroxylin A inhibited NLRP3 inflammasome activation by reducing ROS accumulation. Furthermore, oroxylin A upregulated mitofusin 2 (Mfn2) to resist lipid deposition and mitochondria-derived ROS overproduction. As an upstream mediator of Mfn2, peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1α), a major regulator of mitochondria, was found to promote transcription of Mfn2 under oroxylin A treatment. Our research revealed that oroxylin A could alleviate ALD via PGC-1α/Mfn2 signaling mediated canonical pyroptosis pathway resistance.
Sections du résumé
BACKGROUND
It is well acknowledged that alcoholic liver disease (ALD) is widely prevalent all over the world, characterized by aberrant lipid deposition and excessive oxidative stress in hepatocytes. Recently, pyroptosis, a new type of programmed cell death, has been found in ALD, which provides new ideas for the treatment of ALD.
METHODS
Male ICR mice were treated with the Lieber-De-Carli diet (Dyets) or isocaloric liquid diet for 8 weeks, and binge alcohol model was also used for ALD. Blood and livers were taken to evaluate the efficacy of oroxylin A. The levels of factors related to hepatocyte pyroptosis were measured via western blot analyses, immunofluorescence analyses and quantitative reverse transcriptase in vitro.
RESULT
Our study found that oroxylin A suppressed hepatocyte pyroptosis through a NLRP3 inflammasome dependent-canonical caspase-1 pathway. Results illuminated that oroxylin A inhibited NLRP3 inflammasome activation by reducing ROS accumulation. Furthermore, oroxylin A upregulated mitofusin 2 (Mfn2) to resist lipid deposition and mitochondria-derived ROS overproduction. As an upstream mediator of Mfn2, peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1α), a major regulator of mitochondria, was found to promote transcription of Mfn2 under oroxylin A treatment.
CONCLUSION
Our research revealed that oroxylin A could alleviate ALD via PGC-1α/Mfn2 signaling mediated canonical pyroptosis pathway resistance.
Identifiants
pubmed: 32289481
pii: S0891-5849(19)32537-7
doi: 10.1016/j.freeradbiomed.2020.03.031
pii:
doi:
Substances chimiques
Flavonoids
0
Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
0
Reactive Oxygen Species
0
5,7-dihydroxy-6-methoxy-2-phenylchromen-4-one
53K24Z586G
GTP Phosphohydrolases
EC 3.6.1.-
Mfn2 protein, mouse
EC 3.6.1.-
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
89-102Informations de copyright
Copyright © 2020 Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of competing interest All authors confirm that there is no conflict of interest.