4 research outputs found

    The therapeutic role of NAD+ modulation in fatty liver disease

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    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

    Eliciting the mitochondrial unfolded protein response via NAD+ repletion reverses fatty liver disease

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    With no approved pharmacological treatment, nonalcoholic fatty liver disease (NAFLD) is now the most common cause of chronic liver disease inWestern countries and its worldwide prevalence continues to increase along with the growing obesity epidemic. Here, we show that a high-fat high-sucrose (HFHS) diet, eliciting chronic hepatosteatosis resembling human fatty liver, lowers hepatic nicotinamide adenine dinucleotide (NAD(+)) levels driving reductions in hepatic mitochondrial content, function, and adenosine triphosphate (ATP) levels, in conjunction with robust increases in hepatic weight, lipid content, and peroxidation in C57BL/6J mice. To assess the effect of NAD(+) repletion on the development of steatosis in mice, nicotinamide riboside, a precursor of NAD(+) biosynthesis, was added to theHFHS diet, either as a preventive strategy or as a therapeutic intervention. We demonstrate that NR prevents and reverts NAFLD by inducing a sirtuin (SIRT)1- and SIRT3-dependent mitochondrial unfolded protein response, triggering an adaptive mitohormetic pathway to increase hepatic beta-oxidation and mitochondrial complex content and activity. The cell-autonomous beneficial component of NR treatment was revealed in liver-specific Sirt1 knockout mice (Sirt1(hep-/-)), whereas apolipoprotein E-deficient mice (Apoe(-/-)) challenged with a high-fat high-cholesterol diet affirmed the use of NR in other independent models of NAFLD. Conclusion: Our data warrant the future evaluation of NAD(+) boosting strategies to manage the development or progression of NAFLD

    NAD+ repletion improves muscle function in muscular dystrophy and counters global PARylation

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    Neuromuscular diseases are often caused by inherited mutations that lead to progressive skeletal muscle weakness and degeneration. In diverse populations of normal healthy mice, we observed correlations between the abundance of mRNA transcripts related to mitochondrial biogenesis, the dystrophin-sarcoglycan complex, and nicotinamide adenine dinucleotide (NAD+) synthesis, consistent with a potential role for the essential cofactor NAD+ in protecting muscle from metabolic and structural degeneration. Furthermore, the skeletal muscle transcriptomes of patients with Duchene’s muscular dystrophy (DMD) and other muscle diseases were enriched for various poly[adenosine 5′-diphosphate (ADP)–ribose] polymerases (PARPs) and for nicotinamide N-methyltransferase (NNMT), enzymes that are major consumers of NAD+ and are involved in pleiotropic events, including inflammation. In the mdx mouse model of DMD, we observed significant reductions in muscle NAD+ levels, concurrent increases in PARP activity, and reduced expression of nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme for NAD+ biosynthesis. Replenishing NAD+ stores with dietary nicotinamide riboside supplementation improved muscle function and heart pathology in mdx and mdx/Utr−/− mice and reversed pathology in Caenorhabditis elegans models of DMD. The effects of NAD+ repletion in mdx mice relied on the improvement in mitochondrial function and structural protein expression (α-dystrobrevin and δ-sarcoglycan) and on the reductions in general poly(ADP)-ribosylation, inflammation, and fibrosis. In combination, these studies suggest that the replenishment of NAD+ may benefit patients with muscular dystrophies or other neuromuscular degenerative conditions characterized by the PARP/NNMT gene expression signatures.836

    NAD(+) repletion improves muscle function in muscular dystrophy and counters global PARylation

    No full text
    Neuromuscular diseases are often caused by inherited mutations that lead to progressive skeletal muscle weakness and degeneration. In diverse populations of normal healthy mice, we observed correlations between the abundance of mRNA transcripts related to mitochondrial biogenesis, the dystrophin-sarcoglycan complex, and nicotinamide adenine dinucleotide (NAD(+)) synthesis, consistent with a potential role for the essential cofactor NAD(+) in protecting muscle from metabolic and structural degeneration. Furthermore, the skeletal muscle transcriptomes of patients with Duchene's muscular dystrophy (DMD) and other muscle diseases were enriched for various poly[adenosine 5'-diphosphate (ADP)-ribose] polymerases (PARPs) and for nicotinamide N-methyltransferase (NNMT), enzymes that are major consumers of NAD(+) and are involved in pleiotropic events, including inflammation. In the mdx mouse model of DMD, we observed significant reductions in muscle NAD(+) levels, concurrent increases in PARP activity, and reduced expression of nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme for NAD+ biosynthesis. Replenishing NAD(+) stores with dietary nicotinamide riboside supplementation improved muscle function and heart pathology in mdx and mdx/Utr(-/-)mice and reversed pathology in Caenorhabditis elegans models of DMD. The effects of NAD(+) repletion in mdx mice relied on the improvement in mitochondrial function and structural protein expression (alpha-dystrobrevin and delta-sarcoglycan) and on the reductions in general poly(ADP)-ribosylation, inflammation, and fibrosis. In combination, these studies suggest that the replenishment of NAD(+) may benefit patients with muscular dystrophies or other neuromuscular degenerative conditions characterized by the PARP/NNMT gene expression signatures
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