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

    Research output: Contribution to journalArticle

    72 Scopus citations

    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 - May 2014

    ASJC Scopus subject areas

    • Hepatology

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  • Cite this

    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, A. H., Gao, B., & 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