Sambeat, AudreyRatajczak, JoannaJoffraud, MagaliSanchez-Garcia, Jose L.Giner, Maria P.Valsesia, ArmandGiroud-Gerbetant, JudithValera-Alberni, MiriamCercillieux, AngeliqueBoutant, MarieKulkarni, Sameer S.Moco, SofiaCanto, Caries2019-10-052019-10-052019-10-052019-09-2010.1038/s41467-019-12262-xhttps://infoscience.epfl.ch/handle/20.500.14299/161846WOS:000486995200001Supplementation 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.Multidisciplinary SciencesScience & Technology - Other Topicshepatic gluconeogenesislife-spannad(+)mononucleotidehomeostasisdeficiencyactivationnutrientpathwaydiseasetext::journal::journal article::research article