Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, 63110, USA.
Biogenerator, St. Louis, MO, 63110, USA.
Nat Commun. 2022 Feb 28;13(1):1074. doi: 10.1038/s41467-022-28717-7.
Calorie restriction abates aging and cardiometabolic disease by activating metabolic signaling pathways, including nicotinamide adenine dinucleotide (NAD) biosynthesis and salvage. Nicotinamide phosphoribosyltransferase (NAMPT) is rate-limiting in NAD salvage, yet hepatocyte NAMPT actions during fasting and metabolic duress remain unclear. We demonstrate that hepatocyte NAMPT is upregulated in fasting mice, and in isolated hepatocytes subjected to nutrient withdrawal. Mice lacking hepatocyte NAMPT exhibit defective FGF21 activation and thermal regulation during fasting, and are sensitized to diet-induced glucose intolerance. Hepatocyte NAMPT overexpression induced FGF21 and adipose browning, improved glucose homeostasis, and attenuated dyslipidemia in obese mice. Hepatocyte SIRT1 deletion reversed hepatocyte NAMPT effects on dark-cycle thermogenesis, and hepatic FGF21 expression, but SIRT1 was dispensable for NAMPT insulin-sensitizing, anti-dyslipidemic, and light-cycle thermogenic effects. Hepatocyte NAMPT thus conveys key aspects of the fasting response, which selectively dissociate through hepatocyte SIRT1. Modulating hepatocyte NAD is thus a potential mechanism through which to attenuate fasting-responsive disease.
热量限制通过激活代谢信号通路，包括烟酰胺腺嘌呤二核苷酸（NAD）的生物合成和回收，从而延缓衰老和心血管代谢疾病。烟酰胺磷酸核糖转移酶（NAMPT）是 NAD 回收的限速酶，但在禁食和代谢应激期间，肝细胞 NAMPT 的作用仍不清楚。我们证明，在禁食小鼠和接受营养剥夺的分离肝细胞中，肝细胞 NAMPT 上调。缺乏肝细胞 NAMPT 的小鼠在禁食期间表现出 FGF21 激活和体温调节缺陷，并且对饮食诱导的葡萄糖不耐受敏感。肝细胞 NAMPT 过表达诱导 FGF21 和脂肪褐变，改善葡萄糖稳态，并减轻肥胖小鼠的血脂异常。肝细胞 SIRT1 缺失逆转了肝细胞 NAMPT 对暗周期产热和肝 FGF21 表达的影响，但 SIRT1 对于 NAMPT 胰岛素增敏、抗血脂异常和光周期产热作用是可有可无的。因此，肝细胞 NAMPT 传递了禁食反应的关键方面，这些方面通过肝细胞 SIRT1 选择性分离。调节肝细胞 NAD 可能是减轻与禁食相关疾病的潜在机制。
