Abstract
Supplementation with the NAD+ precursor nicotinamide riboside (NR) ameliorates and prevents a broad array of metabolic and aging disorders in mice. However, little is known about the physiological role of endogenous NR metabolism. We have previously shown that NR kinase 1 (NRK1) is rate-limiting and essential for NR-induced NAD+ synthesis in hepatic cells. To understand the relevance of hepatic NR metabolism, we generated whole body and liver-specific NRK1 knockout mice. Here, we show that NRK1 deficiency leads to decreased gluconeogenic potential and impaired mitochondrial function. Upon high-fat feeding, NRK1 deficient mice develop glucose intolerance, insulin resistance and hepatosteatosis. Furthermore, they are more susceptible to diet-induced liver DNA damage, due to compromised PARP1 activity. Our results demonstrate that endogenous NR metabolism is critical to sustain hepatic NAD+ levels and hinder diet-induced metabolic damage, highlighting the relevance of NRK1 as a therapeutic target for metabolic disorders.
Highlights
Supplementation with the NAD+ precursor nicotinamide riboside (NR) ameliorates and prevents a broad array of metabolic and aging disorders in mice
This work provides evidence that (1) endogenous NR metabolism is required to sustain hepatic NAD+ levels in situations of metabolic damage and lipotoxicity and, (2) the inability to use NR as a NAD+ precursor leads to mitochondrial dysfunction and amplifies the detrimental effects of high-fat diet (HFD)
The observed phenotype is unlikely to originate from a major defect in mitophagy or mtUPR, investigating the exact contribution of NR metabolism to these processes would require an extensive study lying beyond the scope of this manuscript
Summary
Supplementation with the NAD+ precursor nicotinamide riboside (NR) ameliorates and prevents a broad array of metabolic and aging disorders in mice. Upon high-fat feeding, NRK1 deficient mice develop glucose intolerance, insulin resistance and hepatosteatosis They are more susceptible to diet-induced liver DNA damage, due to compromised PARP1 activity. Our results demonstrate that endogenous NR metabolism is critical to sustain hepatic NAD+ levels and hinder diet-induced metabolic damage, highlighting the relevance of NRK1 as a therapeutic target for metabolic disorders. NRK1 is highly expressed in the liver, whereas the NRK2 protein can only be detected in heart and skeletal muscle[13] Taken together, these observations suggest that endogenous NR utilization and NRK1 activity could be essential to sustain hepatic metabolic functions in non-supplemented conditions. At the molecular level, liver-specific NRK1 deletion induces NAD+ depletion leading to decreased PARP1 activity, exacerbating HFD-induced hepatic DNA damage. We demonstrate that NR deficiency cannot be compensated by NAM, arguing that NAD+ precursors are not always exchangeable
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