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

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• 作者：Karim Gariani¹ ; Dongryeol Ryu¹ ; ^&dagger ; ; Keir J. Menzies¹ ; ³ ; ^&dagger ; ; Hyon-Seung Yi⁵ ; Sokrates Stein² ; ⁴ ; Hongbo Zhang¹ ; Alessia Perino² ; Vera Lemos² ; Elena Katsyuba¹ ; Pooja Jha¹ ; Sandrine Vijgen⁷ ; Laura Rubbia-Brandt⁷ ; Yong Kyung Kim⁵ ; Jung Tae Kim⁶ ; Koon Soon Kim⁵ ; Minho Shong⁵ ; Kristina Schoonjans² ; Johan Auwerx¹ ; ^{admin.auwerx@epfl.ch}
• 关键词：Non-alcoholic fatty liver disease ; Poly ADP-ribosylation ; Sirtuin ; PARP inhibitor ; PARylation ; NAD
• 刊名：Journal of Hepatology
• 出版年：2017
• 出版时间：January 2017
• 年：2017
• 卷：66
• 期：1
• 页码：132-141
• 全文大小：2791 K
• 卷排序：66

文摘

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.MethodsAs 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.ResultsThe 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.ConclusionsOur study provides a novel and practical pharmacological approach for treating NAFLD, fueling optimism for potential clinical studies.Lay summaryNon-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.