The therapeutic role of NAD+ modulation in fatty liver disease

Abstract

NAFLD encompasses a disease spectrum ranging from hepatic steatosis to nonalcoholic steatohepatitis (NASH), fibrosis, and finally cirrhosis, which predisposes to the development of hepatocellular carcinoma. With no approved pharmacological treatment, NAFLD is currently the most common etiology of chronic liver disease in western countries and its prevalence continues to growth concurrent to the rising obesity epidemic. SIRT1 may prove to be a critical target for the treatment of NAFLD since it has been demonstrated to induce transcription of genes involved in mitochondrial metabolism and antioxidant protection, while also inhibiting inflammatory and death signaling. In my PhD thesis projects, we aimed to explore the effect of SIRT1 activation through NAD+ modulation in the treatment of NAFLD. Protection against NAFLD by NAD+ repletion. In this study we evaluated the potential of Nicotinamide Riboside (NR) as a therapeutic agent against the development of NAFLD. First, we observed a positive correlation between gene sets for β-oxidation and genes involved in NAD+ biosynthesis in two distinct data sets of healthy human liver samples supporting the function of NAD+ as a coenzyme in key metabolic processes. Then we showed that NAD+ repletion using NR, an NAD+ booster, attenuated mitochondrial dysfunction and prevented and reversed fatty liver development in a several mouse models of NAFLD. Inhibiting PARPs protects against NAFLD development. We hypothesized that overactivation of PARP proteins, NAD+ consuming enzymes that are involved in various cell stress responses, promotes NAD+ depletion in NAFLD. To evaluate this hypothesis, we tested the therapeutic effect of a PARP inhibitor, olaparib in two mouse models of NAFLD. We found that PARP inhibition repletes NAD+ levels, protects against NAFLD and reduces ER-stress and fibrosis. The beneficial effect of PARP was dependent on Sirt1. In summary, our studies demonstrated a major role for NAD+ levels and PARP activity in the development of NAFLD. Repletion of NAD+, by NR administration, or PARP inhibition may therefore represent attractive strategies to counteract the development of NAFLD

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