Liver metabolomics reveals increased oxidative stress and fibrogenic potential in gfrp transgenic mice in response to ionizing radiation.
Although radiation-induced tissue-specific injury is well documented, the underlying molecular changes resulting in organ dysfunction and the consequences thereof on overall metabolism and physiology have not been elucidated. We previously reported the generation and characterization of a transgenic mouse strain that ubiquitously overexpresses Gfrp (GTPH-1 feedback regulatory protein) and exhibits higher oxidative stress, which is a possible result of decreased tetrahydrobiopterin (BH4) bioavailability. In this study, we report genotype-dependent changes in the metabolic profiles of liver tissue after exposure to nonlethal doses of ionizing radiation. Using a combination of untargeted and targeted quantitative mass spectrometry, we report significant accumulation of metabolites associated with oxidative stress, as well as the dysregulation of lipid metabolism in transgenic mice after radiation exposure. The radiation stress seems to exacerbate lipid peroxidation and also results in higher expression of genes that facilitate liver fibrosis, in a manner that is dependent on the genetic background and post-irradiation time interval. These findings suggest the significance of Gfrp in regulating redox homeostasis in response to stress induced by ionizing radiation affecting overall physiology.
Departments of Oncology, ‡Biochemistry, Molecular and Cellular Biology, and ∥Department of Biostatistics, Bioinformatics and Biomathematics, Georgetown University Medical Center , Washington DC 20057, United States.
Amrita K
AK
Cheema
Rupak
R
Pathak
Fereshteh
F
Zandkarimi
Prabhjit
P
Kaur
Lynn
L
Alkhalil
Rajbir
R
Singh
Xiaogang
X
Zhong
Sanchita
S
Ghosh
Nukhet
N
Aykin-Burns
Martin
M
Hauer-Jensen
D000818:Animals; D002352:Carrier Proteins / Q000096:biosynthesis / Q000235:genetics*; D005260:Female; D050356:Lipid Metabolism / Q000528:radiation effects; D015227:Lipid Peroxidation; D008099:Liver / Q000378:metabolism* / Q000528:radiation effects; D008103:Liver Cirrhosis / Q000209:etiology / Q000378:metabolism*; D008297:Male; D055442:Metabolome; D055432:Metabolomics; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D018384:Oxidative Stress; D011833:Radiation Injuries, Experimental / Q000378:metabolism*; D011839:Radiation, Ionizing; D015398:Signal Transduction
D002352:Carrier Proteins; C000592576:GCHFR protein, mouse