Serine and 1-carbon metabolism are required for HIF-mediated protection against retinopathy of prematurity
| Autor: | Charandeep Singh, Jonathan E. Sears, Amit Sharma, George Hoppe, Vincent Tran, Henri Brunengraber, Youstina Bolok, Weilin Song, Leah McCollum |
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| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Glycine Retina Hypoxia-Inducible Factor-Proline Dioxygenases Tissue Culture Techniques Serine Mice 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine medicine Animals Humans Retinopathy of Prematurity Glycolysis Mice Knockout Protein Stability Chemistry Retinal General Medicine Metabolism Hypoxia-Inducible Factor 1 alpha Subunit Isoquinolines Carbon Up-Regulation Cell biology Oxygen Disease Models Animal Methotrexate 030104 developmental biology medicine.anatomical_structure Liver 030220 oncology & carcinogenesis Urea cycle Metabolic Networks and Pathways Ex vivo Research Article |
| Zdroj: | JCI Insight. 4 |
| ISSN: | 2379-3708 |
| DOI: | 10.1172/jci.insight.129398 |
| Popis: | 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 [(13)C(6)] glucose labeling of metabolites in ex vivo retinal explants as well as in vivo [(13)C(3)] 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-1α(2lox/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. |
| Databáze: | OpenAIRE |
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