Hepatic NMNAT1 is required to defend against alcohol-associated fatty liver disease

IF 11.7 1区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES

Science Advances Pub Date : 2025-06-27

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

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Abstract

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.

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肝脏NMNAT1是防御酒精相关脂肪肝疾病所必需的

烟酰胺单核苷酸腺苷转移酶1 （NMNAT1）是一种烟酰胺腺嘌呤二核苷酸（NAD+）合成酶，在press - handler和salvage通路中起调控核NAD+稳态的作用。本研究探讨了NMNAT1在酒精相关性肝病（ALD）中的作用。在酒精相关性肝炎患者的肝脏和ALD小鼠的肝细胞或原代肝细胞中观察到NMNAT1的表达和活性降低。含有7 （FBXW7）调控的干扰素调节因子1 （IRF1）泛素化降解的F-box和WD重复结构域有助于酒精抑制NMNAT1的转录水平。肝脏NMNAT1基因敲除加重了酒精诱导的肝脏NAD+下降和进一步的肝脂肪变性和肝损伤。代谢组学和转录组学相互作用显示，半胱氨酸亚磺酸脱羧酶（CSAD）调节的牛磺酸途径参与了nmnat1破坏ALD的肝脏脂质代谢。肝脏CSAD过表达或牛磺酸供应可减轻肝脏NMNAT1敲除加重的ALD。肝脏NMNAT1缺失抑制nmn保护的ALD。补充肝脏NMNAT1逆转ALD小鼠肝脏脂质积累。这些发现确定了NMNAT1是一种有希望的治疗ALD的靶点。

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来源期刊

Science Advances 综合性期刊-综合性期刊

CiteScore

21.40

自引率

1.50%

发文量

1937

审稿时长

29 weeks

期刊介绍： Science Advances, an open-access journal by AAAS, publishes impactful research in diverse scientific areas. It aims for fair, fast, and expert peer review, providing freely accessible research to readers. Led by distinguished scientists, the journal supports AAAS's mission by extending Science magazine's capacity to identify and promote significant advances. Evolving digital publishing technologies play a crucial role in advancing AAAS's global mission for science communication and benefitting humankind.