Endogenous nicotinamide riboside metabolism protects against diet-induced liver damage

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.

The role of the tryptophan-nicotinamide pathway in a model of severe malnutrition induced liver dysfunction

“…NAFLD mice, hepatocytes with endoplasmic reticulum stress) [55][56][57][58] . However, other studies have found no direct effect of NAM supplementation on NAD+ levels 18,59 . If the extra NAD that is synthesized, is readily used for deacetylation, then you would not see a significant increase.…”

“…After 7 days, malnourished subgroups were treated with modulators of the TRP-NAM pathway until sacrifice on day 14. Nicotinamide, nicotinamide-riboside and tryptophan were given by drinking water in a dose of 160 mg/kg body weight/day, and methionine was included in diets at a concentration of 0.75 g/kg diet 15,59,63 . Nicotinamide, nicotinamide-riboside and tryptophan were provided by Sigma-Aldrich (St. Louis, MO, USA).…”

The NAD Metabolome is Functionally Depressed in Patients Undergoing Liver Transplantation for Alcohol-related Liver Disease

“…This also constitutes the first observation of substantive NR concentration in non-supplemented human tissues. The role of endogenous NR metabolism has been heightened by recent observation that loss of hepatic NRK1 expression depresses liver function and that endogenous hepatic NRK1 expression declines in mice on high fat diet (29,35).…”

“…In particular, in rodent models, supplementation of either NA (43,44) or NR(26) can protect against alcoholic liver injury. On the basis of recent data showing that NR has the highest level of hepatic oral availability of the NAD + precursor vitamins (25), that endogenous NR metabolism protects the liver (29,35) and that high dose NR is safe and potentially valuable in and fatty liver (45), measures to increase NAD + content in human liver might be of clinical benefit. Vitamin B1 supplementation is well established in ArLD, primarily for the prophylaxis or treatment of Wernicke's encephalopathy.…”

“…In rodent models, hepatic carcinogenesis (19), diet-induced steatosis (25), alcohol-induced liver injury (26) and fibrosis (27) can be counteracted by provision of NR, while NA protects against alcoholic fatty liver (11). Moreover, in mice, the condition of postpartum depresses the maternal hepatic NAD metabolome (28) and endogenous metabolism of NR is protective against diet-induced liver damage (29). However, the present understanding of the normal and diseased hepatic NAD + metabolome is based solely on animal models of ArLD.…”