Hepatic NADH reductive stress underlies common variation in metabolic traits

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 and Vamsi K. Mootha ()
Additional contact information
Russell P. Goodman: Massachusetts General Hospital
Andrew L. Markhard: Massachusetts General Hospital
Hardik Shah: Massachusetts General Hospital
Rohit Sharma: Massachusetts General Hospital
Owen S. Skinner: Massachusetts General Hospital
Clary B. Clish: Broad Institute
Amy Deik: Broad Institute
Anupam Patgiri: Massachusetts General Hospital
Yu-Han H. Hsu: Broad Institute
Ricard Masia: Massachusetts General Hospital
Hye Lim Noh: University of Massachusetts Medical School
Sujin Suk: University of Massachusetts Medical School
Olga Goldberger: Massachusetts General Hospital
Joel N. Hirschhorn: Broad Institute
Gary Yellen: Harvard Medical School
Jason K. Kim: University of Massachusetts Medical School
Vamsi K. Mootha: Massachusetts General Hospital

Nature, 2020, vol. 583, issue 7814, 122-126

Abstract: 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’.

Date: 2020
References: Add references at CitEc
Citations: View citations in EconPapers (2)

Downloads: (external link)
https://www.nature.com/articles/s41586-020-2337-2 Abstract (text/html)
Access to the full text of the articles in this series is restricted.

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:nature:v:583:y:2020:i:7814:d:10.1038_s41586-020-2337-2

Ordering information: This journal article can be ordered from
https://www.nature.com/

DOI: 10.1038/s41586-020-2337-2

Access Statistics for this article

Nature is currently edited by Magdalena Skipper

More articles in Nature from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().