Partha Mukhopadhyay1, Béla Horváth2, Mohanraj Rajesh2, Zoltán V Varga2, Karim Gariani3, Dongryeol Ryu3, Zongxian Cao2, Eileen Holovac2, Ogyi Park4, Zhou Zhou4, Ming-Jiang Xu4, Wei Wang4, Grzegorz Godlewski5, Janos Paloczi2, Balazs Tamas Nemeth2, Yuri Persidsky6, Lucas Liaudet7, György Haskó8, Peter Bai9, A Hamid Boulares10, Johan Auwerx3, Bin Gao4, Pal Pacher11. 1. Laboratory of Cardiovascular Physiology and Tissue Injury, National Institutes of Health/NIAAA, Bethesda, MD 20852, USA. Electronic address: mpartha@mail.nih.gov. 2. Laboratory of Cardiovascular Physiology and Tissue Injury, National Institutes of Health/NIAAA, Bethesda, MD 20852, USA. 3. Laboratory of Integrative and Systems Physiology, École Polytechnique Fédérale de Lausanne, CH-1015 Lausanne, Switzerland. 4. Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD 20852, USA. 5. Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD 20852, USA. 6. Department of Pathology and Laboratory Medicine, Temple University School of Medicine, Philadelphia, PA 19140, USA. 7. Department of Intensive Care Medicine, BH 08-621-University Hospital Medical Center, 1011 Lausanne, Switzerland. 8. Department of Surgery and Center for Immunity & Inflammation of Surgery Rutgers, New Jersey Medical School, Newark, NJ 07103, USA. 9. Department of Medical Chemistry, Faculty of Medicine, University of Debrecen, 4032, Hungary; MTA-DE Lendület Laboratory of Cellular Metabolism, Debrecen H-4032, Hungary. 10. The Stanley Scott Cancer Center and Department of Pharmacology, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA. 11. Laboratory of Cardiovascular Physiology and Tissue Injury, National Institutes of Health/NIAAA, Bethesda, MD 20852, USA. Electronic address: pacher@mail.nih.gov.
Abstract
BACKGROUND & AIMS: Mitochondrial dysfunction, oxidative stress, inflammation, and metabolic reprograming are crucial contributors to hepatic injury and subsequent liver fibrosis. Poly(ADP-ribose) polymerases (PARP) and their interactions with sirtuins play an important role in regulating intermediary metabolism in this process. However, there is little research into whether PARP inhibition affects alcoholic and non-alcoholic steatohepatitis (ASH/NASH). METHODS: We investigated the effects of genetic deletion of PARP1 and pharmacological inhibition of PARP in models of early alcoholic steatohepatitis, as well as on Kupffer cell activation in vitro using biochemical assays, real-time PCR, and histological analyses. The effects of PARP inhibition were also evaluated in high fat or methionine and choline deficient diet-induced steatohepatitis models in mice. RESULTS: PARP activity was increased in livers due to excessive alcohol intake, which was associated with decreased NAD+ content and SIRT1 activity. Pharmacological inhibition of PARP restored the hepatic NAD+ content, attenuated the decrease in SIRT1 activation and beneficially affected the metabolic-, inflammatory-, and oxidative stress-related alterations due to alcohol feeding in the liver. PARP1-/- animals were protected against alcoholic steatohepatitis and pharmacological inhibition of PARP or genetic deletion of PARP1 also attenuated Kupffer cell activation in vitro. Furthermore, PARP inhibition decreased hepatic triglyceride accumulation, metabolic dysregulation, or inflammation and/or fibrosis in models of NASH. CONCLUSION: Our results suggests that PARP inhibition is a promising therapeutic strategy in steatohepatitis with high translational potential, considering the availability of PARP inhibitors for clinical treatment of cancer. LAY SUMMARY: Poly(ADP-ribose) polymerases (PARP) are the most abundant nuclear enzymes. The PARP inhibitor olaparib (Lynparza) is a recently FDA-approved therapy for cancer. This study shows that PARP is overactivated in livers of subjects with alcoholic liver disease and that pharmacological inhibition of this enzyme with 3 different PARP inhibitors, including olaparib, attenuates high fat or alcohol induced liver injury, abnormal metabolic alteration, fat accumulation, inflammation and/or fibrosis in preclinical models of liver disease. These results suggest that PARP inhibition is a promising therapeutic strategy in the treatment of alcoholic and non-alcoholic liver diseases. Published by Elsevier B.V.
BACKGROUND & AIMS:Mitochondrial dysfunction, oxidative stress, inflammation, and metabolic reprograming are crucial contributors to hepatic injury and subsequent liver fibrosis. Poly(ADP-ribose) polymerases (PARP) and their interactions with sirtuins play an important role in regulating intermediary metabolism in this process. However, there is little research into whether PARP inhibition affects alcoholic and non-alcoholic steatohepatitis (ASH/NASH). METHODS: We investigated the effects of genetic deletion of PARP1 and pharmacological inhibition of PARP in models of early alcoholic steatohepatitis, as well as on Kupffer cell activation in vitro using biochemical assays, real-time PCR, and histological analyses. The effects of PARP inhibition were also evaluated in high fat or methionine and choline deficient diet-induced steatohepatitis models in mice. RESULTS:PARP activity was increased in livers due to excessive alcohol intake, which was associated with decreased NAD+ content and SIRT1 activity. Pharmacological inhibition of PARP restored the hepatic NAD+ content, attenuated the decrease in SIRT1 activation and beneficially affected the metabolic-, inflammatory-, and oxidative stress-related alterations due to alcohol feeding in the liver. PARP1-/- animals were protected against alcoholic steatohepatitis and pharmacological inhibition of PARP or genetic deletion of PARP1 also attenuated Kupffer cell activation in vitro. Furthermore, PARP inhibition decreased hepatic triglyceride accumulation, metabolic dysregulation, or inflammation and/or fibrosis in models of NASH. CONCLUSION: Our results suggests that PARP inhibition is a promising therapeutic strategy in steatohepatitis with high translational potential, considering the availability of PARP inhibitors for clinical treatment of cancer. LAY SUMMARY:Poly(ADP-ribose) polymerases (PARP) are the most abundant nuclear enzymes. The PARP inhibitor olaparib (Lynparza) is a recently FDA-approved therapy for cancer. This study shows that PARP is overactivated in livers of subjects with alcoholic liver disease and that pharmacological inhibition of this enzyme with 3 different PARP inhibitors, including olaparib, attenuates high fat or alcohol induced liver injury, abnormal metabolic alteration, fat accumulation, inflammation and/or fibrosis in preclinical models of liver disease. These results suggest that PARP inhibition is a promising therapeutic strategy in the treatment of alcoholic and non-alcoholic liver diseases. Published by Elsevier B.V.
Authors: Nathan A Berger; Valerie C Besson; A Hamid Boulares; Alexander Bürkle; Alberto Chiarugi; Robert S Clark; Nicola J Curtin; Salvatore Cuzzocrea; Ted M Dawson; Valina L Dawson; György Haskó; Lucas Liaudet; Flavio Moroni; Pál Pacher; Peter Radermacher; Andrew L Salzman; Solomon H Snyder; Francisco Garcia Soriano; Robert P Strosznajder; Balázs Sümegi; Raymond A Swanson; Csaba Szabo Journal: Br J Pharmacol Date: 2017-03-26 Impact factor: 8.739