Nestlé Research, EPFL Innovation Park, 1015, Lausanne, Switzerland.
School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne (EPFL), 1015, Lausanne, Switzerland.
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.
补充烟酰胺核糖（NR）的前体烟酰胺核苷（NR）可改善和预防小鼠广泛的代谢和衰老紊乱。然而，内源性 NR 代谢的生理作用知之甚少。我们之前曾表明，NR 激酶 1（NRK1）是限速酶，对肝细胞中 NR 诱导的 NAD 合成至关重要。为了了解肝 NR 代谢的相关性，我们生成了全身和肝特异性 NRK1 敲除小鼠。在这里，我们表明 NRK1 缺乏会导致糖异生潜力降低和线粒体功能受损。在高脂肪饮食喂养下，NRK1 缺陷小鼠会出现葡萄糖不耐受、胰岛素抵抗和肝脂肪变性。此外，由于 PARP1 活性受损，它们更容易发生饮食诱导的肝 DNA 损伤。我们的研究结果表明，内源性 NR 代谢对于维持肝 NAD 水平和阻止饮食诱导的代谢损伤至关重要，这凸显了 NRK1 作为代谢紊乱治疗靶点的重要性。
