Song Won-Suk, Shen Xiyu, Du Kang, Ramirez Cuauhtemoc B, Park Sang Hee, Cao Yang, Le Johnny, Bae Hosung, Kim Joohwan, Chun Yujin, Khong Nikki Joyce, Kim Marie, Jung Sunhee, Choi Wonsuk, Lopez Miranda L, Said Zaid, Song Zehan, Lee Sang-Guk, Nicholas Dequina, Sasaki Yo, Milbrandt Jeffrey, Imagawa David K, Skowronska-Krawczyk Dorota, Chen Danica, Lee Gina, Jang Cholsoon, Yang Qin
Department of Biological Chemistry, Center for Epigenetics and Metabolism, Chao Family Comprehensive Cancer Center, University of California, Irvine, School of Medicine, Irvine, CA 92697, USA.
Department of Medicine, Physiology and Biophysics, University of California, Irvine, School of Medicine, Irvine, CA 92697, USA.
Cell Metab. 2025 Jul 1;37(7):1499-1514.e4. doi: 10.1016/j.cmet.2025.04.007. Epub 2025 May 1.
Liver-derived circulating nicotinamide from nicotinamide adenine dinucleotide (NAD) catabolism primarily feeds systemic organs for NAD synthesis. We surprisingly found that, despite blunted hepatic NAD and nicotinamide production in liver-specific nicotinamide nucleotide adenylyltransferase 1 (NMNAT1) deletion mice (liver-specific knockout [LKO]), circulating nicotinamide and extra-hepatic organs' NAD are unaffected. Metabolomics reveals a massive accumulation of a novel molecule in the LKO liver, which we identify as nicotinic acid riboside (NaR). We further demonstrate cytosolic 5'-nucleotidase II (NT5C2) as the NaR-producing enzyme. The liver releases NaR to the bloodstream, and kidneys take up NaR to synthesize NAD through nicotinamide riboside kinase 1 (NRK1) and replenish circulating nicotinamide. Serum NaR levels decline with aging, whereas oral NaR supplementation in aged mice boosts serum nicotinamide and multi-organ NAD, including kidneys, and reduces kidney inflammation and albuminuria. Thus, the liver-kidney axis maintains systemic NAD homeostasis via circulating NaR, and NaR supplement ameliorates aging-associated NAD decline and kidney dysfunction.
肝脏中烟酰胺腺嘌呤二核苷酸（NAD）分解代谢产生的循环烟酰胺主要为全身各器官提供用于NAD合成的原料。我们惊讶地发现，尽管肝脏特异性烟酰胺核苷酸腺苷酸转移酶1（NMNAT1）缺失小鼠（肝脏特异性敲除[LKO]）的肝脏NAD和烟酰胺生成减少，但循环烟酰胺和肝外器官的NAD并未受到影响。代谢组学研究显示，LKO小鼠肝脏中一种新分子大量蓄积，我们将其鉴定为烟酸核糖苷（NaR）。我们进一步证明胞质5'-核苷酸酶II（NT5C2）是产生NaR的酶。肝脏将NaR释放到血液中，肾脏摄取NaR，通过烟酰胺核糖激酶1（NRK1）合成NAD，并补充循环烟酰胺。血清NaR水平随年龄增长而下降，而老年小鼠口服补充NaR可提高血清烟酰胺和包括肾脏在内的多器官NAD水平，并减轻肾脏炎症和蛋白尿。因此，肝肾轴通过循环NaR维持全身NAD稳态，补充NaR可改善与衰老相关的NAD下降和肾功能障碍。
