Titre
Poly (ADP-ribose) polymerase-1 is a key mediator of liver inflammation and fibrosis.
Type
article
Institution
UNIL/CHUV/Unisanté + institutions partenaires
Périodique
Auteur(s)
Mukhopadhyay, P.
Auteure/Auteur
Rajesh, M.
Auteure/Auteur
Cao, Z.
Auteure/Auteur
Horváth, B.
Auteure/Auteur
Park, O.
Auteure/Auteur
Wang, H.
Auteure/Auteur
Erdelyi, K.
Auteure/Auteur
Holovac, E.
Auteure/Auteur
Wang, Y.
Auteure/Auteur
Liaudet, L.
Auteure/Auteur
Hamdaoui, N.
Auteure/Auteur
Lafdil, F.
Auteure/Auteur
Haskó, G.
Auteure/Auteur
Szabo, C.
Auteure/Auteur
Boulares, A.H.
Auteure/Auteur
Gao, B.
Auteure/Auteur
Pacher, P.
Auteure/Auteur
Liens vers les personnes
Liens vers les unités
ISSN
1527-3350
Statut éditorial
Publié
Date de publication
2014
Volume
59
Numéro
5
Première page
1998
Dernière page/numéro d’article
2009
Peer-reviewed
Oui
Langue
anglais
Notes
Publication types: Journal Article ; Research Support, N.I.H., Extramural ; Research Support, N.I.H., Intramural Publication Status: ppublish
Résumé
Poly (ADP-ribose) polymerase 1 (PARP-1) is a constitutive enzyme, the major isoform of the PARP family, which is involved in the regulation of DNA repair, cell death, metabolism, and inflammatory responses. Pharmacological inhibitors of PARP provide significant therapeutic benefits in various preclinical disease models associated with tissue injury and inflammation. However, our understanding the role of PARP activation in the pathophysiology of liver inflammation and fibrosis is limited. In this study we investigated the role of PARP-1 in liver inflammation and fibrosis using acute and chronic models of carbon tetrachloride (CCl4 )-induced liver injury and fibrosis, a model of bile duct ligation (BDL)-induced hepatic fibrosis in vivo, and isolated liver-derived cells ex vivo. Pharmacological inhibition of PARP with structurally distinct inhibitors or genetic deletion of PARP-1 markedly attenuated CCl4 -induced hepatocyte death, inflammation, and fibrosis. Interestingly, the chronic CCl4 -induced liver injury was also characterized by mitochondrial dysfunction and dysregulation of numerous genes involved in metabolism. Most of these pathological changes were attenuated by PARP inhibitors. PARP inhibition not only prevented CCl4 -induced chronic liver inflammation and fibrosis, but was also able to reverse these pathological processes. PARP inhibitors also attenuated the development of BDL-induced hepatic fibrosis in mice. In liver biopsies of subjects with alcoholic or hepatitis B-induced cirrhosis, increased nitrative stress and PARP activation was noted.
CONCLUSION: The reactive oxygen/nitrogen species-PARP pathway plays a pathogenetic role in the development of liver inflammation, metabolism, and fibrosis. PARP inhibitors are currently in clinical trials for oncological indications, and the current results indicate that liver inflammation and liver fibrosis may be additional clinical indications where PARP inhibition may be of translational potential.
CONCLUSION: The reactive oxygen/nitrogen species-PARP pathway plays a pathogenetic role in the development of liver inflammation, metabolism, and fibrosis. PARP inhibitors are currently in clinical trials for oncological indications, and the current results indicate that liver inflammation and liver fibrosis may be additional clinical indications where PARP inhibition may be of translational potential.
PID Serval
serval:BIB_19EAC92AF60E
PMID
Open Access
Oui
Date de création
2014-07-11T16:14:49.991Z
Date de création dans IRIS
2025-05-20T20:07:15Z
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Nom
BIB_19EAC92AF60E.P001.pdf
Version du manuscrit
preprint
Taille
3.02 MB
Format
Adobe PDF
PID Serval
serval:BIB_19EAC92AF60E.P001
URN
urn:nbn:ch:serval-BIB_19EAC92AF60E8
Somme de contrôle
(MD5):51329946288878ed46b5bc3a8e98358c