Poly (ADP-ribose) polymerase-1 is a key mediator of liver inflammation and fibrosis

Partha Mukhopadhyay, Mohanraj Rajesh, Zongxian Cao, Béla Horváth, Ogyi Park, Hua Wang, Katalin Erdelyi, Eileen Holovac, Yuping Wang, Lucas Liaudet, Nabila Hamdaoui, Fouad Lafdil, György Haskó, Csaba Szabo, A. Hamid Boulares, Bin Gao, Pal Pacher

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)1998-2009
Number of pages12
JournalHepatology
Volume59
Issue number5
DOIs
StatePublished - 2014

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Inflammation Mediators
Liver Cirrhosis
Inflammation
Fibrosis
Liver
Bile Ducts
Ligation
Wounds and Injuries
Pharmacology
Alcoholic Hepatitis
Reactive Nitrogen Species
Carbon Tetrachloride
Pathologic Processes
Poly (ADP-Ribose) Polymerase-1
Hepatitis B
DNA Repair
Hepatocytes
Reactive Oxygen Species
Protein Isoforms
Cell Death

ASJC Scopus subject areas

  • Hepatology

Cite this

Mukhopadhyay, P., Rajesh, M., Cao, Z., Horváth, B., Park, O., Wang, H., ... Pacher, P. (2014). Poly (ADP-ribose) polymerase-1 is a key mediator of liver inflammation and fibrosis. Hepatology, 59(5), 1998-2009. https://doi.org/10.1002/hep.26763

Poly (ADP-ribose) polymerase-1 is a key mediator of liver inflammation and fibrosis. / Mukhopadhyay, Partha; Rajesh, Mohanraj; Cao, Zongxian; Horváth, Béla; Park, Ogyi; Wang, Hua; Erdelyi, Katalin; Holovac, Eileen; Wang, Yuping; Liaudet, Lucas; Hamdaoui, Nabila; Lafdil, Fouad; Haskó, György; Szabo, Csaba; Boulares, A. Hamid; Gao, Bin; Pacher, Pal.

In: Hepatology, Vol. 59, No. 5, 2014, p. 1998-2009.

Research output: Contribution to journalArticle

Mukhopadhyay, P, Rajesh, M, Cao, Z, Horváth, B, Park, O, Wang, H, Erdelyi, K, Holovac, E, Wang, Y, Liaudet, L, Hamdaoui, N, Lafdil, F, Haskó, G, Szabo, C, Boulares, AH, Gao, B & Pacher, P 2014, 'Poly (ADP-ribose) polymerase-1 is a key mediator of liver inflammation and fibrosis', Hepatology, vol. 59, no. 5, pp. 1998-2009. https://doi.org/10.1002/hep.26763
Mukhopadhyay P, Rajesh M, Cao Z, Horváth B, Park O, Wang H et al. Poly (ADP-ribose) polymerase-1 is a key mediator of liver inflammation and fibrosis. Hepatology. 2014;59(5):1998-2009. https://doi.org/10.1002/hep.26763
Mukhopadhyay, Partha ; Rajesh, Mohanraj ; Cao, Zongxian ; Horváth, Béla ; Park, Ogyi ; Wang, Hua ; Erdelyi, Katalin ; Holovac, Eileen ; Wang, Yuping ; Liaudet, Lucas ; Hamdaoui, Nabila ; Lafdil, Fouad ; Haskó, György ; Szabo, Csaba ; Boulares, A. Hamid ; Gao, Bin ; Pacher, Pal. / Poly (ADP-ribose) polymerase-1 is a key mediator of liver inflammation and fibrosis. In: Hepatology. 2014 ; Vol. 59, No. 5. pp. 1998-2009.
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AU - Rajesh, Mohanraj

AU - Cao, Zongxian

AU - Horváth, Béla

AU - Park, Ogyi

AU - Wang, Hua

AU - Erdelyi, Katalin

AU - Holovac, Eileen

AU - Wang, Yuping

AU - Liaudet, Lucas

AU - Hamdaoui, Nabila

AU - Lafdil, Fouad

AU - Haskó, György

AU - Szabo, Csaba

AU - Boulares, A. Hamid

AU - Gao, Bin

AU - Pacher, Pal

PY - 2014

Y1 - 2014

N2 - 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.

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