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肝脏NADH还原应激是代谢性状常见变异的基础
作者:小柯机器人 发布时间:2020/5/29 13:07:44

近日,美国哈佛医学院Vamsi K. Mootha研究团队发现,肝脏NADH还原应激是代谢性状常见变异的基础。2020年5月27日,《自然》杂志在线发表了这项成果。

研究人员发现,在体内应用的乳酸短杆菌(Lb)NOX1,这是一种细菌中产生水的NADH氧化酶,能够用于评估直接降低小鼠肝细胞内NADH/NAD+比例的代谢后果。通过将这种遗传工具与代谢组学相结合,研究人员将循环α-羟基丁酸酯水平鉴定为肝细胞NADH/NAD+比升高(也称为还原性应激)的标志。
 
在人类中,循环α-羟基丁酸酯水平的升高以前与葡萄糖耐量降低、胰岛素抵抗和线粒体疾病相关,并与GCKR5中常见的遗传变异相关,这以突变也与许多看似不同的代谢性状相关。使用LbNOX,研究人员证明了NADH还原应激介导GCKR变化对许多代谢性状的影响,包括循环甘油三酸酯水平、葡萄糖耐受量和FGF21水平。
 
这项工作将肝脏NADH/NAD+比例的升高鉴定为潜在的代谢参数,这一参数由人类遗传变异决定,并对关键的代谢特征和疾病起因果关系。此外,它还强调了LbNOX等遗传工具在“因果性代谢”研究中的作用。
 
据悉,细胞内NADH/NAD+比例是生物化学的基础,但人们对其在体内代谢所贡献的程度(反应还是驱动)却知之甚少。
 
附:英文原文
 
Title: Hepatic NADH reductive stress underlies common variation in metabolic traits

Author: Russell P. Goodman, Andrew L. Markhard, Hardik Shah, Rohit Sharma, Owen S. Skinner, Clary B. Clish, Amy Deik, Anupam Patgiri, Yu-Han H. Hsu, Ricard Masia, Hye Lim Noh, Sujin Suk, Olga Goldberger, Joel N. Hirschhorn, Gary Yellen, Jason K. Kim, Vamsi K. Mootha

Issue&Volume: 2020-05-27

Abstract: The cellular NADH/NAD+ ratio is fundamental to biochemistry, but the extent to which it reflects versus drives metabolic physiology in vivo is poorly understood. Here we report the in vivo application of Lactobacillus brevis (Lb)NOX1, a bacterial water-forming NADH oxidase, to assess the metabolic consequences of directly lowering the hepatic cytosolic NADH/NAD+ ratio in mice. By combining this genetic tool with metabolomics, we identify circulating α-hydroxybutyrate levels as a robust marker of an elevated hepatic cytosolic NADH/NAD+ ratio, also known as reductive stress. In humans, elevations in circulating α-hydroxybutyrate levels have previously been associated with impaired glucose tolerance2, insulin resistance3 and mitochondrial disease4, and are associated with a common genetic variant in GCKR5, which has previously been associated with many seemingly disparate metabolic traits. Using LbNOX, we demonstrate that NADH reductive stress mediates the effects of GCKR variation on many metabolic traits, including circulating triglyceride levels, glucose tolerance and FGF21 levels. Our work identifies an elevated hepatic NADH/NAD+ ratio as a latent metabolic parameter that is shaped by human genetic variation and contributes causally to key metabolic traits and diseases. Moreover, it underscores the utility of genetic tools such as LbNOX to empower studies of ‘causal metabolism’.

DOI: 10.1038/s41586-020-2337-2

Source: https://www.nature.com/articles/s41586-020-2337-2

期刊信息

Nature:《自然》,创刊于1869年。隶属于施普林格·自然出版集团,最新IF:43.07
官方网址:http://www.nature.com/
投稿链接:http://www.nature.com/authors/submit_manuscript.html