title: PARP inhibition protects against alcoholic and non-alcoholic steatohepatitis.
abstract: 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).
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: Laboratory of Cardiovascular Physiology and Tissue Injury, National Institutes of Health/NIAAA, Bethesda, MD 20852, USA. Electronic address: mpartha@mail.nih.gov.
authors.forename: Partha
authors.initials: P
authors.lastname: Mukhopadhyay
authors.affiliation: Laboratory of Cardiovascular Physiology and Tissue Injury, National Institutes of Health/NIAAA, Bethesda, MD 20852, USA.
authors.forename: Béla
authors.initials: B
authors.lastname: Horváth
authors.affiliation: Laboratory of Cardiovascular Physiology and Tissue Injury, National Institutes of Health/NIAAA, Bethesda, MD 20852, USA.
authors.forename: Mohanraj
authors.initials: M
authors.lastname: Rajesh
authors.affiliation: Laboratory of Cardiovascular Physiology and Tissue Injury, National Institutes of Health/NIAAA, Bethesda, MD 20852, USA.
authors.forename: Zoltán V
authors.initials: ZV
authors.lastname: Varga
authors.affiliation: Laboratory of Integrative and Systems Physiology, École Polytechnique Fédérale de Lausanne, CH-1015 Lausanne, Switzerland.
authors.forename: Karim
authors.initials: K
authors.lastname: Gariani
authors.affiliation: Laboratory of Integrative and Systems Physiology, École Polytechnique Fédérale de Lausanne, CH-1015 Lausanne, Switzerland.
authors.forename: Dongryeol
authors.initials: D
authors.lastname: Ryu
authors.affiliation: Laboratory of Cardiovascular Physiology and Tissue Injury, National Institutes of Health/NIAAA, Bethesda, MD 20852, USA.
authors.forename: Zongxian
authors.initials: Z
authors.lastname: Cao
authors.affiliation: Laboratory of Cardiovascular Physiology and Tissue Injury, National Institutes of Health/NIAAA, Bethesda, MD 20852, USA.
authors.forename: Eileen
authors.initials: E
authors.lastname: Holovac
authors.affiliation: Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD 20852, USA.
authors.forename: Ogyi
authors.initials: O
authors.lastname: Park
authors.affiliation: Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD 20852, USA.
authors.forename: Zhou
authors.initials: Z
authors.lastname: Zhou
authors.affiliation: Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD 20852, USA.
authors.forename: Ming-Jiang
authors.initials: MJ
authors.lastname: Xu
authors.affiliation: Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD 20852, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.affiliation: Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD 20852, USA.
authors.forename: Grzegorz
authors.initials: G
authors.lastname: Godlewski
authors.affiliation: Laboratory of Cardiovascular Physiology and Tissue Injury, National Institutes of Health/NIAAA, Bethesda, MD 20852, USA.
authors.forename: Janos
authors.initials: J
authors.lastname: Paloczi
authors.affiliation: Laboratory of Cardiovascular Physiology and Tissue Injury, National Institutes of Health/NIAAA, Bethesda, MD 20852, USA.
authors.forename: Balazs Tamas
authors.initials: BT
authors.lastname: Nemeth
authors.affiliation: Department of Pathology and Laboratory Medicine, Temple University School of Medicine, Philadelphia, PA 19140, USA.
authors.forename: Yuri
authors.initials: Y
authors.lastname: Persidsky
authors.affiliation: Department of Intensive Care Medicine, BH 08-621-University Hospital Medical Center, 1011 Lausanne, Switzerland.
authors.forename: Lucas
authors.initials: L
authors.lastname: Liaudet
authors.affiliation: Department of Surgery and Center for Immunity & Inflammation of Surgery Rutgers, New Jersey Medical School, Newark, NJ 07103, USA.
authors.forename: György
authors.initials: G
authors.lastname: Haskó
authors.affiliation: Department of Medical Chemistry, Faculty of Medicine, University of Debrecen, 4032, Hungary; MTA-DE Lendület Laboratory of Cellular Metabolism, Debrecen H-4032, Hungary.
authors.forename: Peter
authors.initials: P
authors.lastname: Bai
authors.affiliation: The Stanley Scott Cancer Center and Department of Pharmacology, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA.
authors.forename: A Hamid
authors.initials: AH
authors.lastname: Boulares
authors.affiliation: Laboratory of Integrative and Systems Physiology, École Polytechnique Fédérale de Lausanne, CH-1015 Lausanne, Switzerland.
authors.forename: Johan
authors.initials: J
authors.lastname: Auwerx
authors.affiliation: Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD 20852, USA.
authors.forename: Bin
authors.initials: B
authors.lastname: Gao
authors.affiliation: Laboratory of Cardiovascular Physiology and Tissue Injury, National Institutes of Health/NIAAA, Bethesda, MD 20852, USA. Electronic address: pacher@mail.nih.gov.
authors.forename: Pal
authors.initials: P
authors.lastname: Pacher
mesh_terms: D000818:Animals; D059305:Diet, High-Fat / Q000009:adverse effects; D004195:Disease Models, Animal; D005227:Fatty Acids / Q000378:metabolism; D005235:Fatty Liver, Alcoholic / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control*; D006801:Humans; D007728:Kupffer Cells / Q000187:drug effects / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009243:NAD / Q000378:metabolism; D000073039:Nitrosative Stress / Q000187:drug effects; D065626:Non-alcoholic Fatty Liver Disease / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control*; D018384:Oxidative Stress / Q000187:drug effects; D010616:Phenanthrenes / Q000494:pharmacology; D010793:Phthalazines / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D000071137:Poly (ADP-Ribose) Polymerase-1 / Q000172:deficiency / Q000235:genetics; D000067856:Poly(ADP-ribose) Polymerase Inhibitors / Q000494:pharmacology*; D011804:Quinolines / Q000494:pharmacology; D056564:Sirtuin 1 / Q000378:metabolism
chemical_list: D005227:Fatty Acids; C434926:N-(oxo-5,6-dihydrophenanthridin-2-yl)-N,N-dimethylacetamide hydrochloride; D010616:Phenanthrenes; D010793:Phthalazines; D010879:Piperazines; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011804:Quinolines; C447244:rel-(3S, 5R, 6S, SR, 8aR,12aR)-8-acetoxy-6-butyl-3-isothiocyanatodecahydropyrido(2,1)quinoline; D009243:NAD; C499321:Parp1 protein, mouse; D000071137:Poly (ADP-Ribose) Polymerase-1; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1; C531550:olaparib
keywords: Alcohols; Fatty liver; Inflammation; Kupffer cells; Mitochondria; NAD(+); NASH; Oxidative stress; Reactive oxygen species