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Serine and 1-carbon metabolism are required for HIF-mediated protection against retinopathy of prematurity
Charandeep Singh, … , Henri Brunengraber, Jonathan E. Sears
Charandeep Singh, … , Henri Brunengraber, Jonathan E. Sears
Published July 25, 2019
Citation Information: JCI Insight. 2019;4(14):e129398. https://doi.org/10.1172/jci.insight.129398.
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Research Article Angiogenesis Metabolism

Serine and 1-carbon metabolism are required for HIF-mediated protection against retinopathy of prematurity

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Abstract

We determined which metabolic pathways are activated by hypoxia-inducible factor 1–mediated (HIF-1–mediated) protection against oxygen-induced retinopathy (OIR) in newborn mice, the experimental correlate to retinopathy of prematurity, a leading cause of infant blindness. HIF-1 coordinates the change from oxidative to glycolytic metabolism and mediates flux through serine and 1-carbon metabolism (1CM) in hypoxic and cancer cells. We used untargeted metabolite profiling in vivo to demonstrate that hypoxia mimesis activates serine/1CM. Both [13C6] glucose labeling of metabolites in ex vivo retinal explants as well as in vivo [13C3] serine labeling of metabolites followed in liver lysates strongly suggest that retinal serine is primarily derived from hepatic glycolytic carbon and not from retinal glycolytic carbon in newborn pups. In HIF-1α2lox/2lox albumin-Cre–knockout mice, reduced or near-0 levels of serine/glycine further demonstrate the hepatic origin of retinal serine. Furthermore, inhibition of 1CM by methotrexate blocked HIF-mediated protection against OIR. This demonstrated that 1CM participates in protection induced by HIF-1 stabilization. The urea cycle also dominated pathway enrichment analyses of plasma samples. The dependence of retinal serine on hepatic HIF-1 and the upregulation of the urea cycle emphasize the importance of the liver to remote protection of the retina.

Authors

Charandeep Singh, George Hoppe, Vincent Tran, Leah McCollum, Youstina Bolok, Weilin Song, Amit Sharma, Henri Brunengraber, Jonathan E. Sears

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Figure 1

Multivariate statistical analysis of metabolite features indicates difference in PBS (control) versus Roxadustat (treated) hyperoxic mice, in plasma and retina metabolome.

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Multivariate statistical analysis of metabolite features indicates diffe...
All the data in this figure are from mice dissected on postnatal day 10. Metabolites from retina (n = 4, each group) and plasma (n = 6, each group) of these mice were extracted and analyzed using LC-MS/MS. Multidimensional data were analyzed using PCA (A–D). The size of the dot represents DModX value for each sample. DModX represents distance of each observation to the model plane and helps in determination of potential outliers, which in our case were absent. (A) PCA score plot of positive ionization mode plasma metabolite features of principal component 1 (PC1) versus PC2. (B) PCA score plot of negative ionization mode plasma data. (C) PCA score plot of positive ionization mode retina data. (D) PCA score plot of negative ionization mode retina data. RXD, Roxadustat.

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