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Hepatic NADH reductive stress underlies common variation in metabolic traits.
Authors Goodman RP, Markhard AL, Shah H, Sharma R, Skinner OS, Clish CB, Deik A, Patgiri
A, Hsu YH, Masia R, Noh HL, Suk S, Goldberger O, Hirschhorn JN, Yellen G, Kim
JK, Mootha VK
Submitted By Submitted Externally on 9/28/2020
Status Published
Journal Nature
Year 2020
Date Published 7/1/2020
Volume : Pages 583 : 122 - 126
PubMed Reference 32461692
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 a-hydroxybutyrate levels as a robust marker of an elevated hepatic
cytosolic NADH/NAD+ ratio, also known as reductive stress. In humans, elevations
in circulating a-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'.


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