Ding Qinchao, Cao Feiwei, Zhuge Hui, Lai Shanglei, Cao Wenjing, Wei Haibin, Guo Rui, Qiu Jiannan, Song Qing, Pei Liuhua, Li Chaolan, Si Caijuan, Sun Zhaoli, Song Zhenyuan, Dou Xiaobing, Li Songtao
School of Public Health, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, PR. China.
School of Life Science, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, PR. China.
Sci Adv. 2025 Jun 27;11(26):eadt6195. doi: 10.1126/sciadv.adt6195.
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.
烟酰胺单核苷酸腺苷酸转移酶1（NMNAT1）是普赖斯-汉德勒途径和补救途径中的一种烟酰胺腺嘌呤二核苷酸（NAD）合成酶，它调控着细胞核内的NAD稳态。本研究调查了NMNAT1在酒精性肝病（ALD）中的作用。在酒精性肝炎患者的肝脏以及ALD小鼠的肝脏或原代肝细胞中，观察到NMNAT1的表达和活性降低。含F-box和WD重复结构域7（FBXW7）调节的干扰素调节因子1（IRF1）泛素化降解导致了酒精对NMNAT1转录水平的抑制。肝脏NMNAT1基因敲除加剧了酒精诱导的肝脏NAD下降以及进一步的肝脏脂肪变性和肝损伤。代谢组学和转录组学相互作用表明，半胱氨酸亚磺酸脱羧酶（CSAD）调节的牛磺酸途径参与了ALD中NMNAT1破坏的肝脏脂质代谢。肝脏CSAD过表达或牛磺酸供应减轻了肝脏NMNAT1基因敲除加剧的ALD。肝脏NMNAT1缺失抑制了NMN对ALD的保护作用。补充肝脏NMNAT1可逆转ALD小鼠的肝脏脂质积累。这些发现确定NMNAT1是ALD一个有前景的治疗靶点。
