Endogenous nicotinamide riboside metabolism protects against diet-induced liver damage

Nat Commun. 2019 Sep 20;10(1):4291. doi: 10.1038/s41467-019-12262-x.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blood Glucose
  • DNA Damage
  • Diet, High-Fat / adverse effects*
  • Disease Models, Animal
  • Gene Knockout Techniques
  • Genetic Predisposition to Disease / genetics
  • Glucose Intolerance
  • Hepatocytes / metabolism
  • Insulin Resistance
  • Lipid Metabolism
  • Liver / metabolism
  • Liver Diseases / genetics
  • Liver Diseases / pathology
  • Liver Diseases / prevention & control*
  • Male
  • Metabolic Syndrome / genetics
  • Metabolic Syndrome / prevention & control
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • NAD / metabolism
  • Niacinamide / analogs & derivatives*
  • Niacinamide / genetics
  • Niacinamide / metabolism
  • Niacinamide / pharmacology
  • Phosphotransferases (Alcohol Group Acceptor) / genetics*
  • Protective Agents / metabolism*
  • Protective Agents / pharmacology*
  • Pyridinium Compounds


  • Blood Glucose
  • Protective Agents
  • Pyridinium Compounds
  • nicotinamide-beta-riboside
  • NAD
  • Niacinamide
  • Phosphotransferases (Alcohol Group Acceptor)
  • Nmrk1 protein, mouse