Radiation-Induced Metabolic Shifts in the Hepatic Parenchyma: Findings from 18F-FDG PET Imaging and Tissue NMR Metabolomics in a Mouse Model for Hepatocellular Carcinoma
Abstract
:1. Introduction
2. Results
2.1. 18F-FDG Uptake in Irradiated and Not-Irradiated Liver Parenchyma
2.2. Metabolic Changes in Irradiated and Not-Irradiated Liver Parenchyma
2.3. Markers of Inflammation and Gluconeogenesis in Irradiated and Not-Irradiated Liver Parenchyma
2.4. Assessment of Liver Enzymes in Irradiated Mice Bearing Orthotopic HCC
2.5. Alterations in Hepatic Metabolic Pathways in Response to Irradiation
3. Discussion
3.1. Metabolic Switch to Glycolysis Following Irradiation of the Liver Parenchyma
3.2. Inflammatory Response in Irradiated Liver Parenchyma
3.3. Bystander Effects in the Left Liver Lobe
3.4. Future Research Directions
4. Materials and Methods
4.1. Experimental Design
4.2. Animal Model and Procedures for Irradiation
4.3. 18F-FDG PET/CT Imaging Protocol and Analysis
4.4. Collection and Extraction of the Liver Tissue for NMR Metabolomics
4.5. NMR Metabolomics Data Processing
4.6. Serum Biomarkers of Liver Damage
4.7. Immunohistochemical Staining of Inflammatory Markers
4.8. RNA Extraction and Gene Expression Analysis
4.9. Statistical Analysis
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Metabolite | VIP Score | Fold Change (|RT/no-RT| > 1.1) | p | Metabolite | VIP Score | Fold change (|RT/no-RT| > 1.1) | p |
---|---|---|---|---|---|---|---|
Right liver | Day 1 | Day 3 | |||||
Glucose | 3.456 | 16.930 | 0.003 | Pyruvate | 1.818 | 6.996 | 0.008 |
Sucrose | 2.244 | 13.483 | 0.015 | Glutamate | 1.043 | 3.487 | 0.024 |
Galactarate | 1.396 | 2.523 | 0.003 | Sucrose | 1.153 | 2.812 | 0.019 |
Galactitol | 1.931 | 4.776 | 0.001 | Malonate | 0.879 | 0.565 | 1.6 × 10−4 |
Pyridoxine | 0.836 | 0.512 | 0.006 | ||||
Choline | 0.955 | 0.479 | 0.009 | ||||
Niacinamide | 1.244 | 0.345 | 1.7 × 10−7 | ||||
Hypoxanthine | 1.763 | 0.341 | 0.028 | ||||
Betaine | 1.449 | 0.252 | 1.4 × 10−4 | ||||
Guanidoacetate | 2.690 | 0.121 | 0.001 | ||||
Sarcosine | 1.992 | 0.090 | 3.8 × 10−4 | ||||
Glycocholate | 2.190 | 0.059 | 2.0 × 10−4 | ||||
Left liver | Day 1 | Day 3 | |||||
Glucose | 2.561 | 17.774 | 0.008 | Fumarate | 1.108 | 1.844 | 0.001 |
Malonate | 2.597 | 9.836 | 0.001 | Niacinamide | 0.981 | 0.577 | 0.005 |
Succinate | 2.437 | 3.979 | 0.004 | Riboflavin | 1.062 | 0.452 | 0.029 |
Galactitol | 1.539 | 3.506 | 0.001 | Succinate | 1.200 | 0.428 | 0.008 |
Glycylproline | 1.350 | 3.018 | 1.7 × 10−4 | Succinylacetone | 1.326 | 0.415 | 0.043 |
Galactarate | 1.404 | 2.866 | 0.001 | Betaine | 1.492 | 0.364 | 3.2 × 10−4 |
Alanine | 1.185 | 2.093 | 0.018 | Sarcosine | 1.448 | 0.349 | 0.002 |
N-Methylhydantoin | 0.919 | 1.832 | 0.049 | Guanidoacetate | 2.401 | 0.335 | 0.036 |
Anserine | 0.613 | 1.433 | 0.046 |
Experimental Design | Number of Animals | ||||
---|---|---|---|---|---|
Post-irradiaton | 1 day | 3 day | |||
Longitudinal imaging data | FDG PET | 1RT | 5 | 5 | |
no-RT | 5 | 5 | |||
Time-points data collection | NMR metabolomics | 1RT | 6 | 6 | |
no-RT | 6 | 6 | |||
Biomarkers of liver damage | 1RT | 3 | 3 | ||
no-RT | 3 | 3 | |||
Cytokines qPCR | 1RT | ≥3 | ≥3 | ||
no-RT | ≥3 | ≥3 | |||
Gluconeogenesis qPCR | 1RT | ≥3 | ≥3 | ||
no-RT | ≥3 | ≥3 |
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Chung, Y.-H.; Tsai, C.-K.; Yu, C.-F.; Wang, W.-L.; Yang, C.-L.; Hong, J.-H.; Yen, T.-C.; Chen, F.-H.; Lin, G. Radiation-Induced Metabolic Shifts in the Hepatic Parenchyma: Findings from 18F-FDG PET Imaging and Tissue NMR Metabolomics in a Mouse Model for Hepatocellular Carcinoma. Molecules 2021, 26, 2573. https://doi.org/10.3390/molecules26092573
Chung Y-H, Tsai C-K, Yu C-F, Wang W-L, Yang C-L, Hong J-H, Yen T-C, Chen F-H, Lin G. Radiation-Induced Metabolic Shifts in the Hepatic Parenchyma: Findings from 18F-FDG PET Imaging and Tissue NMR Metabolomics in a Mouse Model for Hepatocellular Carcinoma. Molecules. 2021; 26(9):2573. https://doi.org/10.3390/molecules26092573
Chicago/Turabian StyleChung, Yi-Hsiu, Cheng-Kun Tsai, Ching-Fang Yu, Wan-Ling Wang, Chung-Lin Yang, Ji-Hong Hong, Tzu-Chen Yen, Fang-Hsin Chen, and Gigin Lin. 2021. "Radiation-Induced Metabolic Shifts in the Hepatic Parenchyma: Findings from 18F-FDG PET Imaging and Tissue NMR Metabolomics in a Mouse Model for Hepatocellular Carcinoma" Molecules 26, no. 9: 2573. https://doi.org/10.3390/molecules26092573