Format

Send to

Choose Destination
J Hepatol. 2017 Jan;66(1):132-141. doi: 10.1016/j.jhep.2016.08.024. Epub 2016 Sep 20.

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

Author information

1
Laboratory of Integrative and Systems Physiology, École Polytechnique Fédérale de Lausanne, CH-1015 Lausanne, Switzerland.
2
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.
3
Research Center for Endocrine and Metabolic Diseases, Chungnam National University School of Medicine, Daejeon 35015, South Korea.
4
Metabolic Signaling, École Polytechnique Fédérale de Lausanne, CH-1015 Lausanne, Switzerland; Center for Molecular Cardiology, University of Zurich, Wagistrasse 12, CH-8952 Schlieren, Switzerland.
5
Metabolic Signaling, École Polytechnique Fédérale de Lausanne, CH-1015 Lausanne, Switzerland.
6
Division of Clinical Pathology, Geneva University Hospital, CH-1211, Switzerland.
7
Department of Medical Science, Chungnam National University School of Medicine, Daejeon 35015, South Korea.
8
Laboratory of Integrative and Systems Physiology, École Polytechnique Fédérale de Lausanne, CH-1015 Lausanne, Switzerland. Electronic address: admin.auwerx@epfl.ch.

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.

KEYWORDS:

NAD; Non-alcoholic fatty liver disease; PARP inhibitor; PARylation; Poly ADP-ribosylation; Sirtuin

PMID:
27663419
DOI:
10.1016/j.jhep.2016.08.024
[Indexed for MEDLINE]
Free full text

Supplemental Content

Full text links

Icon for Elsevier Science
Loading ...
Support Center