Inhibiting poly ADP-ribosylation increases fatty acid oxidation and protects against fatty liver disease.

Abstract

BACKGROUND & AIMS:

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.

METHODS:

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.

RESULTS:

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.

CONCLUSIONS:

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

LAY SUMMARY:

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.

• Authors: Karim Gariani, Dongryeol Ryu, Keir J Menzies, Hyon-Seung Yi, Sokrates Stein, Hongbo Zhang, Alessia Perino, Vera Lemos, Elena Katsyuba, Pooja Jha, Sandrine Vijgen, Laura Rubbia-Brandt, Yong Kyung Kim, Jung Tae Kim, Koon Soon Kim, Minho Shong, Kristina Schoonjans, Johan Auwerx
• Journal: Journal of hepatology (J Hepatol) Vol. 66 Issue 1 Pg. 132-141 (01 2017) ISSN: 1600-0641 [Electronic] Netherlands
• PMID: 27663419 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2016 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Chemical References

• Phthalazines
• Piperazines
• Poly(ADP-ribose) Polymerase Inhibitors
• Poly(ADP-ribose) Polymerases
• olaparib

Topics

• Animals
• Disease Models, Animal
• Lipid Metabolism
• Liver (metabolism, pathology)
• Mice
• Non-alcoholic Fatty Liver Disease (drug therapy, metabolism, pathology)
• Oxidation-Reduction
• Phthalazines (pharmacology)
• Piperazines (pharmacology)
• Poly(ADP-ribose) Polymerase Inhibitors (pharmacology)
• Poly(ADP-ribose) Polymerases (metabolism)