Loss of hepatic Nmnat1 has no impact on diet-induced fatty liver disease
Loss of hepatic Nmnat1 has no impact on diet-induced fatty liver disease
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肝脏 Nmnat1 的缺失对饮食诱发的脂肪肝没有影响
DOI：
10.1016/j.bbrc.2022.10.072
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发表时间：
2022
影响因子：
3.1
通讯作者：
Nakagawa Takashi
中科院分区：
文献类型：
--
作者：
Iqbal Tooba;Nawaz Allah;Karim Mariam;Yaku Keisuke;Hikosaka Keisuke;Matsumoto Michihiro;Nakagawa Takashi
烟酰胺腺嘌呤二核苷酸（NAD+）是参与多种细胞过程的氧化还原反应的生物分子，具有治疗非酒精性脂肪性肝病（NAFLD）和非酒精性脂肪性肝炎（NASH）的潜力。烟酰胺单核苷酸腺苷酰转移酶（Nmnat 1）是NAD+生物合成酶之一，在所有NAD+代谢途径中起着核心作用，对胚胎发育至关重要。然而，Nmnat 1在代谢病理学中的功能，特别是在NAFLD和NASH的发展和进展中的功能仍然未被探索。首先，我们产生了肝脏Nmnat 1敲除（H-Nmnat 1 −/−）小鼠，以研究Nmnat 1的生理功能，发现H-Nmnat 1 −/−小鼠的NAD+水平显着低于对照小鼠。然而，H-Nmnat 1 −/−小鼠表现正常，代谢活性相当。接下来，我们使用三种不同的饮食诱导的NASH模型来评估Nmant 1在代谢紊乱中的病理生理学作用，并发现Nmnat 1的肝脏卢什在肥胖状态下减少了总NAD+的35%-40%。然而，我们对表型变异的分析发现，在H-Nmnat 1 −/−小鼠的所有NASH模型中，身体组成、基因表达和肝脏组织学相当。我们还发现，老年H-Nmnat 1 −/−小鼠表现出与对照小鼠相当的肝脏表型。这些发现表明，Nmnat 1有一个冗余的病理生理肥胖引起的肝脏疾病。
Nicotinamide adenine dinucleotide (NAD+), a biological molecule integral to redox reactions involved in multiple cellular processes, has the potential to treat nonalcoholic fatty liver diseases (NAFLDs) and nonalcoholic steatohepatitis (NASH). Nicotinamide mononucleotide adenylyltransferase (Nmnat1), one of the NAD+biosynthesizing enzymes, plays a central role in all NAD+metabolic pathways and it is vital to embryonic development. However, the function of Nmnat1 in metabolic pathology and, specifically, in the development and progression of NAFLD and NASH remains unexplored. First, we generated hepatic Nmnat1 knockout (H-Nmnat1−/−) mice to investigate the physiological function of Nmnat1 and found that NAD+levels were significantly lower in H-Nmnat1−/−mice than control mice. However, H-Nmnat1−/−mice appeared normal with comparable metabolic activity. Next, we used three different diet-induced NASH models to assess the pathophysiological role of Nmant1 in metabolic disorders and discovered that hepatic loos of Nmnat1 decreased 35%–40% of total NAD+in an obese state. Nevertheless, our analysis of phenotypic variations found comparable body composition, gene expression, and liver histology in all NASH models in H-Nmnat1−/−mice. We also found that aged H-Nmnat1−/−mice exhibited comparable liver phenotypes with control mice. These findings suggest that Nmnat1 has a redundancy to the pathophysiology of obesity-induced hepatic disorders.