Inhibition of ethanol-induced eNAMPT secretion attenuates liver ferroptosis through BAT-Liver communication

作者：Yujia Zhou, Nengzhi Pang, Wenli Li, Qiuyan Li, Jing Luo, Yingying Gu, Qianrong Hu, Yijie Ding, Yan Sun, Jie Pan, Mengqi Gao, Ying Xiao, Sixi Ma, Yanxu Hao, Huichun Xing, E Fang, Wenhua Ling, Zhenfeng Zhang, Lili Yang · 发表于：Redox Biology · 年份：2024 · DOI：10.1016/j.redox.2024.103274 · 被引用次数：10 · 研究领域：Adipose Tissue and Metabolism、Alcohol Consumption and Health Effects、Heme Oxygenase-1 and Carbon Monoxide

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 attenuate...