Inhibiting poly ADP-ribosylation increases fatty acid oxidation and protects against fatty liver disease.
To date, no pharmacological therapy has been approved for non-alcoholic fatty liver disease (NAFLD). The aim of the present study was to evaluate the therapeutic potential of poly ADP-ribose polymerase (PARP) inhibitors in mouse models of NAFLD.



As poly ADP-ribosylation (PARylation) of proteins by PARPs consumes nicotinamide adenine dinucleotide (NAD+), we hypothesized that overactivation of PARPs drives NAD+depletion in NAFLD. Therefore, we assessed the effectiveness of PARP inhibition to replenish NAD+and activate NAD+-dependent sirtuins, hence improving hepatic fatty acid oxidation. To do this, we examined the preventive and therapeutic benefits of the PARP inhibitor (PARPi), olaparib, in different models of NAFLD.



The induction of NAFLD in C57BL/6J mice using a high-fat high-sucrose (HFHS)-diet increased PARylation of proteins by PARPs. As such, increased PARylation was associated with reduced NAD+levels and mitochondrial function and content, which was concurrent with elevated hepatic lipid content. HFHS diet supplemented with PARPi reversed NAFLD through repletion of NAD+, increasing mitochondrial biogenesis and β-oxidation in liver. Furthermore, PARPi reduced reactive oxygen species, endoplasmic reticulum stress and fibrosis. The benefits of PARPi treatment were confirmed in mice fed with a methionine- and choline-deficient diet and in mice with lipopolysaccharide-induced hepatitis; PARP activation was attenuated and the development of hepatic injury was delayed in both models. Using Sirt1hep-/-mice, the beneficial effects of a PARPi-supplemented HFHS diet were found to be Sirt1-dependent.



Our study provides a novel and practical pharmacological approach for treating NAFLD, fueling optimism for potential clinical studies.



Non-alcoholic fatty liver disease (NAFLD) is now considered to be the most common liver disease in the Western world and has no approved pharmacological therapy. PARP inhibitors given as a treatment in two different mouse models of NAFLD confer a protection against its development. PARP inhibitors may therefore represent a novel and practical pharmacological approach for treating NAFLD.
Laboratory of Integrative and Systems Physiology, École Polytechnique Fédérale de Lausanne, CH-1015 Lausanne, Switzerland.
Karim
K
Gariani
Laboratory of Integrative and Systems Physiology, École Polytechnique Fédérale de Lausanne, CH-1015 Lausanne, Switzerland.
Dongryeol
D
Ryu
Laboratory of Integrative and Systems Physiology, École Polytechnique Fédérale de Lausanne, CH-1015 Lausanne, Switzerland; Interdisciplinary School of Health Sciences, University of Ottawa Brain and Mind Research Institute, 451 Smyth Rd, K1H 8M5 Ottawa, Canada.
Keir J
KJ
Menzies
Research Center for Endocrine and Metabolic Diseases, Chungnam National University School of Medicine, Daejeon 35015, South Korea.
Hyon-Seung
HS
Yi
Metabolic Signaling, École Polytechnique Fédérale de Lausanne, CH-1015 Lausanne, Switzerland; Center for Molecular Cardiology, University of Zurich, Wagistrasse 12, CH-8952 Schlieren, Switzerland.
Sokrates
S
Stein
Laboratory of Integrative and Systems Physiology, École Polytechnique Fédérale de Lausanne, CH-1015 Lausanne, Switzerland.
Hongbo
H
Zhang
Metabolic Signaling, École Polytechnique Fédérale de Lausanne, CH-1015 Lausanne, Switzerland.
Alessia
A
Perino
Metabolic Signaling, École Polytechnique Fédérale de Lausanne, CH-1015 Lausanne, Switzerland.
Vera
V
Lemos
Laboratory of Integrative and Systems Physiology, École Polytechnique Fédérale de Lausanne, CH-1015 Lausanne, Switzerland.
Elena
E
Katsyuba
Laboratory of Integrative and Systems Physiology, École Polytechnique Fédérale de Lausanne, CH-1015 Lausanne, Switzerland.
Pooja
P
Jha
Division of Clinical Pathology, Geneva University Hospital, CH-1211, Switzerland.
Sandrine
S
Vijgen
Division of Clinical Pathology, Geneva University Hospital, CH-1211, Switzerland.
Laura
L
Rubbia-Brandt
Research Center for Endocrine and Metabolic Diseases, Chungnam National University School of Medicine, Daejeon 35015, South Korea.
Yong Kyung
YK
Kim
Department of Medical Science, Chungnam National University School of Medicine, Daejeon 35015, South Korea.
Jung Tae
JT
Kim
Research Center for Endocrine and Metabolic Diseases, Chungnam National University School of Medicine, Daejeon 35015, South Korea.
Koon Soon
KS
Kim
Research Center for Endocrine and Metabolic Diseases, Chungnam National University School of Medicine, Daejeon 35015, South Korea.
Minho
M
Shong
Metabolic Signaling, École Polytechnique Fédérale de Lausanne, CH-1015 Lausanne, Switzerland.
Kristina
K
Schoonjans
Laboratory of Integrative and Systems Physiology, École Polytechnique Fédérale de Lausanne, CH-1015 Lausanne, Switzerland. Electronic address: admin.auwerx@epfl.ch.
Johan
J
Auwerx
D000818:Animals; D004195:Disease Models, Animal; D050356:Lipid Metabolism; D008099:Liver / Q000378:metabolism / Q000473:pathology; D051379:Mice; D065626:Non-alcoholic Fatty Liver Disease / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D010084:Oxidation-Reduction; D010793:Phthalazines / Q000494:pharmacology*; D010879:Piperazines / Q000494:pharmacology*; D000067856:Poly(ADP-ribose) Polymerase Inhibitors / Q000494:pharmacology; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism
D010793:Phthalazines; D010879:Piperazines; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases; C531550:olaparib
NAD; Non-alcoholic fatty liver disease; PARP inhibitor; PARylation; Poly ADP-ribosylation; Sirtuin