Inhibition of ethanol-induced eNAMPT secretion attenuates liver ferroptosis through BAT-Liver communication
Yujia Zhou,
Nengzhi Pang,
Wenli Li,
Qiuyan Li,
Jing Luo,
Yingying Gu,
Qianrong Hu,
Yi Jie Ding,
Yan Sun,
Jie Pan,
Mengqi Gao,
Ying Xiao,
Sixi Ma,
Yanxu Hao,
Huichun Xing,
Evendro Fei Fang,
Wenhua Ling,
Zhenfeng Zhang,
Lili Yang
Affiliations
Yujia Zhou
Department of Nutrition, Guangdong Provincial Key Laboratory of Food, Nutrition and Health, School of Public Health, Sun Yat-sen University, Guangzhou, Guangdong, China; State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China
Nengzhi Pang
Department of Nutrition, Guangdong Provincial Key Laboratory of Food, Nutrition and Health, School of Public Health, Sun Yat-sen University, Guangzhou, Guangdong, China
Wenli Li
Department of Nutrition, Guangdong Provincial Key Laboratory of Food, Nutrition and Health, School of Public Health, Sun Yat-sen University, Guangzhou, Guangdong, China; Department of Immunization Programs, Guangzhou Huadu District Center for Disease Control and Prevention, Guangzhou, Guangdong, China
Qiuyan Li
Department of Nutrition, Guangdong Provincial Key Laboratory of Food, Nutrition and Health, School of Public Health, Sun Yat-sen University, Guangzhou, Guangdong, China
Jing Luo
Department of Nutrition, Guangdong Provincial Key Laboratory of Food, Nutrition and Health, School of Public Health, Sun Yat-sen University, Guangzhou, Guangdong, China
Yingying Gu
Department of Nutrition, Guangdong Provincial Key Laboratory of Food, Nutrition and Health, School of Public Health, Sun Yat-sen University, Guangzhou, Guangdong, China
Qianrong Hu
Department of Nutrition, Guangdong Provincial Key Laboratory of Food, Nutrition and Health, School of Public Health, Sun Yat-sen University, Guangzhou, Guangdong, China; Department of Women Health Care, Guangzhou Baiyun District Maternal and Child Health Hospital, Guangzhou, Guangdong, China
Yi Jie Ding
Department of Nutrition, Guangdong Provincial Key Laboratory of Food, Nutrition and Health, School of Public Health, Sun Yat-sen University, Guangzhou, Guangdong, China
Yan Sun
Department of Nutrition, Guangdong Provincial Key Laboratory of Food, Nutrition and Health, School of Public Health, Sun Yat-sen University, Guangzhou, Guangdong, China
Jie Pan
Department of Nutrition, Guangdong Provincial Key Laboratory of Food, Nutrition and Health, School of Public Health, Sun Yat-sen University, Guangzhou, Guangdong, China
Mengqi Gao
Department of Nutrition, Guangdong Provincial Key Laboratory of Food, Nutrition and Health, School of Public Health, Sun Yat-sen University, Guangzhou, Guangdong, China
Ying Xiao
Department of Nutrition, Guangdong Provincial Key Laboratory of Food, Nutrition and Health, School of Public Health, Sun Yat-sen University, Guangzhou, Guangdong, China
Sixi Ma
Department of Nutrition, Guangdong Provincial Key Laboratory of Food, Nutrition and Health, School of Public Health, Sun Yat-sen University, Guangzhou, Guangdong, China
Yanxu Hao
Center of Liver Diseases Division 3, Beijing Ditan Hospital, Capital Medical University, Beijing, China
Huichun Xing
Center of Liver Diseases Division 3, Beijing Ditan Hospital, Capital Medical University, Beijing, China; Peking University Ditan Teaching Hospital, Beijing, China
Evendro Fei Fang
Department of Clinical Molecular Biology, University of Oslo and Akershus University Hospital, 1478, Lørenskog, Norway
Wenhua Ling
Department of Nutrition, Guangdong Provincial Key Laboratory of Food, Nutrition and Health, School of Public Health, Sun Yat-sen University, Guangzhou, Guangdong, China
Zhenfeng Zhang
Department of Radiology, Translational Medicine Center and Guangdong Provincial Education Department, Key Laboratory of Nano-Immunoregulation Tumor Microenvironment, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China; Corresponding author.
Lili Yang
Department of Nutrition, Guangdong Provincial Key Laboratory of Food, Nutrition and Health, School of Public Health, Sun Yat-sen University, Guangzhou, Guangdong, China; Corresponding author. Department of Nutrition, School of Public Health, Sun Yat-sen University, Guangzhou, 510080, China.
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.
