BACKGROUND & AIMS Extracellular nicotinamide phosphoribosyltransferase (eNAMPT) has long been recognized as an adipokine. However, the exact role of eNAMPT in alcoholic liver disease (ALD) and its relevance to brown adipose tissue (BAT) remain largely unknown. This study aimed to evaluate the impact of eNAMPT on liver function and the underlying mechanisms involved in BAT-Liver communication. METHODS Serum eNAMPT levels were detected in the serum of both ALD patients and mice. Chronic and binge ethanol feeding was used to induce alcoholic liver injury in mice. An eNAMPT antibody, a coculture model of brown adipocytes and hepatocytes, and BAT-specific Nampt knockdown mice were used to investigate the role of eNAMPT in ALD. RESULTS Serum eNAMPT levels are elevated in ALD patients and are significantly positively correlated with the liver injury index. In ALD mice, neutralizing eNAMPT reduced the elevated levels of circulating eNAMPT induced by ethanol and attenuated liver injury. In vitro experiments revealed that eNAMPT induced hepatocyte ferroptosis through the TLR4-dependent mitochondrial ROS-induced ferritinophagy pathway. Furthermore, ethanol stimulated eNAMPT secretion from brown adipocytes but not from other adipocytes. In the coculture model, ethanol-induced release of eNAMPT from brown adipocytes promoted hepatocyte ferroptosis. In BAT-specific Nampt-knockdown mice, ethanol-induced eNAMPT secretion was significantly reduced, and alcoholic liver injury were attenuated. These effects can be reversed by intraperitoneal injection of eNAMPT. CONCLUSION Inhibition of ethanol-induced eNAMPT secretion from BAT attenuates liver injury and ferroptosis. Our study reveals a previously uncharacterized critical role of eNAMPT-mediated BAT-Liver communication in ALD and highlights its potential as a therapeutic target.

中文翻译：

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抑制乙醇诱导的 eNAMPT 分泌可通过 BAT-肝脏通讯减轻肝铁死亡。


背景与目的细胞外烟酰胺磷酸核糖基转移酶（eNAMPT）长期以来被认为是一种脂肪因子。然而，eNAMPT 在酒精性肝病 (ALD) 中的确切作用及其与棕色脂肪组织 (BAT) 的相关性仍然很大程度上未知。本研究旨在评估 eNAMPT 对肝功能的影响以及 BAT-肝脏通讯的潜在机制。方法检测ALD患者和小鼠血清中eNAMPT水平。长期和暴饮暴食乙醇可诱导小鼠酒精性肝损伤。使用 eNAMPT 抗体、棕色脂肪细胞和肝细胞共培养模型以及 BAT 特异性 Nampt 敲低小鼠来研究 eNAMPT 在 ALD 中的作用。结果 ALD患者血清eNAMPT水平升高，且与肝损伤指数显着正相关。在 ALD 小鼠中，中和 eNAMPT 可以降低乙醇引起的循环 eNAMPT 水平升高，并减轻肝损伤。体外实验表明，eNAMPT 通过 TLR4 依赖性线粒体 ROS 诱导的铁蛋白自噬途径诱导肝细胞铁死亡。此外，乙醇刺激棕色脂肪细胞分泌eNAMPT，但不刺激其他脂肪细胞分泌eNAMPT。在共培养模型中，乙醇诱导棕色脂肪细胞释放 eNAMPT 促进肝细胞铁死亡。在 BAT 特异性 Nampt 敲除小鼠中，乙醇诱导的 eNAMPT 分泌显着减少，酒精性肝损伤也减轻。这些效应可以通过腹腔注射 eNAMPT 来逆转。结论 抑制乙醇诱导的 BAT 分泌 eNAMPT 可减轻肝损伤和铁死亡。 我们的研究揭示了 eNAMPT 介导的 BAT-肝脏通讯在 ALD 中的先前未表征的关键作用，并强调了其作为治疗靶点的潜力。