Hepatic NMNAT1 is required to defend against alcohol-associated fatty liver disease
- Qinchao Ding
- Feiwei Cao
- Hui Zhuge
- Shanglei Lai
- Wenjing Cao
- Haibin Wei
- Rui Guo
- Jiannan Qiu
- Qing Song
- Liuhua Pei
- Chaolan Li
- Caijuan Si
- Zhaoli Sun
- Zhenyuan Song
- Xiaobing Dou
- Songtao Li
2025-07-25
Nicotinamide mononucleotide adenylyltransferase 1 (NMNAT1), a nicotinamide adenine dinucleotide (NAD + ) synthetase in Preiss-Handler and salvage pathways, governs nuclear NAD + homeostasis. This study investigated the role of NMNAT1 in alcohol-associated liver disease (ALD). Decreased NMNAT1 expression and activity were observed in the liver of patients with alcohol-associated hepatitis and either liver or primary hepatocytes from ALD mice. F-box and WD repeat domain containing 7 (FBXW7)–regulated interferon regulatory factor 1 (IRF1) ubiquitination degradation contributed to the alcohol-inhibited NMNAT1 transcriptional level. Hepatic NMNAT1 knockout aggravated alcohol-induced hepatic NAD + decline and further hepatic steatosis and liver injury. Metabolomics and transcriptomics interaction revealed that the cysteine sulfinic acid decarboxylase (CSAD)–regulated taurine pathway was involved in NMNAT1-disrupted hepatic lipid metabolism in ALD. Hepatic CSAD overexpression or taurine supply attenuated hepatic NMNAT1 knockout–aggravated ALD. Hepatic NMNAT1 loss inhibited NMN-protected ALD. Replenishing hepatic NMNAT1 reversed liver lipid accumulation in ALD mice. These findings identified NMNAT1 as a promising therapeutic target for ALD.