Hepatic NADH reductive stress underlies common variation in metabolic traits

doi:10.1038/s41586-020-2337-2

GSTDTAP > 地球科学

DOI	10.1038/s41586-020-2337-2
	Hepatic NADH reductive stress underlies common variation in metabolic traits
	Skov, Laurits 1,2; Coll Macia, Moises 1; Sveinbjoernsson, Gardar 3; Mafessoni, Fabrizio 2; Lucotte, Elise A.1; Einarsdottir, Margret S.3; Jonsson, Hakon 3; Halldorsson, Bjarni 3,4; Gudbjartsson, Daniel F.3; Helgason, Agnar 3,5; Schierup, Mikkel Heide 1; Stefansson, Kari 3,6
	2020-04-22
发表期刊	NATURE
ISSN	0028-0836
EISSN	1476-4687
出版年	2020
卷号	583 期号:7814 页码:122-+
文章类型	Article
语种	英语
国家	USA
英文关键词	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 alpha-hydroxybutyrate levels as a robust marker of an elevated hepatic cytosolic NADH/NAD(+) ratio, also known as reductive stress. In humans, elevations in circulating alpha-hydroxybutyrate levels have previously been associated with impaired glucose tolerance(2), insulin resistance(3) and mitochondrial disease(4), and are associated with a common genetic variant in GCKR(5), 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' . The authors identify an increased hepatic NADH/NAD(+) ratio as an underlying metabolic parameter that is shaped by human genetic variation and contributes causally to key metabolic traits and diseases.
领域	地球科学 ; 气候变化 ; 资源环境
收录类别	SCI-E
WOS记录号	WOS:000535878900003
WOS关键词	INSULIN-RESISTANCE ; MISSENSE VARIANT ; GLUCOSE ; FGF21 ; TRIGLYCERIDE ; MANIPULATION ; ASSOCIATION ; SENSITIVITY ; EXPRESSION ; ETHANOL
WOS类目	Multidisciplinary Sciences
WOS研究方向	Science & Technology - Other Topics
引用统计
文献类型	期刊论文
条目标识符	http://119.78.100.173/C666/handle/2XK7JSWQ/281548
专题	地球科学资源环境科学气候变化
作者单位	1.Aarhus Univ, Bioinformat Res Ctr, Aarhus, Denmark; 2.Max Planck Inst Evolutionary Anthropol, Leipzig, Germany; 3.Amgen Inc, deCODE Genet, Reykjavik, Iceland; 4.Reykjavik Univ, Sch Sci & Engn, Reykjavik, Iceland; 5.Univ Iceland, Dept Anthropol, Reykjavik, Iceland; 6.Univ Iceland, Fac Med, Sch Hlth Sci, Reykjavik, Iceland
推荐引用方式 GB/T 7714	Skov, Laurits,Coll Macia, Moises,Sveinbjoernsson, Gardar,et al. Hepatic NADH reductive stress underlies common variation in metabolic traits[J]. NATURE,2020,583(7814):122-+.
APA	Skov, Laurits.,Coll Macia, Moises.,Sveinbjoernsson, Gardar.,Mafessoni, Fabrizio.,Lucotte, Elise A..,...&Stefansson, Kari.(2020).Hepatic NADH reductive stress underlies common variation in metabolic traits.NATURE,583(7814),122-+.
MLA	Skov, Laurits,et al."Hepatic NADH reductive stress underlies common variation in metabolic traits".NATURE 583.7814(2020):122-+.