Abstract：
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.
摘要：
烟酰胺腺嘌呤二核苷酸(NAD+),与多个细胞过程中涉及的氧化还原反应不可或缺的生物分子，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（Nmnat1），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,Nmnat1在代谢病理学中的功能，具体来说,在NAFLD和NASH的发展和进展中仍未被探索。首先,我们制作了肝脏Nmnat1敲除（H-Nmnat1-/-）小鼠以研究Nmnat1的生理功能，发现H-Nmnat1-/-小鼠的NAD水平显着低于对照小鼠。然而,H-Nmnat1-/-小鼠表现正常,具有相当的代谢活性。接下来,我们使用三种不同的饮食诱导的NASH模型来评估Nmant1在代谢紊乱中的病理生理作用,并发现在肥胖状态下,Nmnat1的肝脏Loos减少了总NAD+的35%-40%.然而，我们对表型变异的分析发现了相当的身体成分，基因表达，和H-Nmnat1-/-小鼠的所有NASH模型中的肝组织学。我们还发现，老年H-Nmnat1-/-小鼠表现出与对照小鼠相当的肝脏表型。这些发现表明Nmnat1对肥胖引起的肝病的病理生理学具有冗余性。
