Toxicant-Induced Metabolic Alterations in Lipid and Amino Acid Pathways Are Predictive of Acute Liver Toxicity in Rats
Abstract
:1. Introduction
2. Results
2.1. Common Genes That Changed Significantly Are Highly Correlated between Toxicants
2.2. Toxicant-Induced Changes in Gene Expression Predict Liver Injury Phenotypes
2.3. Correlation between Plasma Metabolite Profiles
2.4. Toxicants Differed in Altering Hepatic Fluxes in Central Carbon Metabolism
2.5. Identification of Metabolic Changes in Liver Metabolism Associated with Liver Toxicity
2.6. Common Changes in Amino Acid and Lipid Metabolism as Potential Signatures of Liver Injury
3. Discussion
4. Materials and Methods
4.1. Animals and Toxicant Dose Determination
4.2. Studies for Measuring Changes in Liver Gene-Expression and Plasma Metabolic Profiles
4.3. Analysis of RNA-Sequencing and Metabolomic Data
4.4. Tracer Labeling Studies for Measuring Metabolic Flux and Metabolic Flux Analysis
4.5. Rat Metabolic Network and Algorithm for Data Integration and Metabolite Predictions
4.6. KEGG Pathway Analysis
4.7. Liver Injury Module Activation Score
Supplementary Materials
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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Main Pathway | Subordinate Pathway | 10 h: APAP | 10 h: BB | 5 h: CCl4 | |||
---|---|---|---|---|---|---|---|
Genes | AFC z-score | Genes | AFC z-score | Genes | AFC z-score | ||
Lipid | Glycerophospholipid metabolism | 28 | 1.42 | 26 | 1.75 | 21 | 0.10 |
Glycerolipid metabolism | 18 | 0.31 | 15 | 2.84 | 14 | −0.97 | |
Steroid biosynthesis | 12 | −4.42 | 13 | −4.09 | 6 | −1.58 | |
Steroid hormone biosynthesis | 26 | −3.49 | 11 | −1.01 | 11 | −0.90 | |
Fatty acid metabolism | 14 | −1.89 | 17 | −1.83 | 12 | −1.96 | |
Biosynthesis of unsaturated fatty acids | 10 | −1.23 | 13 | −0.21 | 7 | −1.63 | |
Fatty acid degradation | 14 | −0.03 | 12 | −0.07 | 8 | −2.06 | |
Arachidonic acid metabolism | 15 | −0.42 | 12 | −0.71 | |||
Fatty acid elongation | 8 | 1.08 | 9 | 1.30 | |||
Sphingolipid metabolism | 12 | 0.96 | 13 | −1.81 | |||
Ether lipid metabolism | 7 | −0.96 | 12 | 0.03 | |||
Fatty acid biosynthesis | 5 | −1.57 | 5 | −0.93 | |||
Primary bile acid biosynthesis | 5 | 0.57 | 5 | −1.49 | |||
AA | Glycine, serine, and threonine metabolism | 17 | 1.63 | 7 | 1.15 | 14 | 1.51 |
Cysteine and methionine metabolism | 17 | 2.16 | 13 | 1.47 | 7 | 1.26 | |
Arginine and proline metabolism | 12 | 0.45 | 12 | 0.40 | 12 | 1.30 | |
Glutathione metabolism | 17 | 0.42 | 8 | 0.76 | 13 | 2.94 | |
Alanine, aspartate, and glutamate metabolism | 11 | 2.28 | 7 | 2.15 | 11 | 0.55 | |
Tryptophan metabolism | 15 | −3.63 | 10 | −1.46 | 11 | −1.99 | |
Arginine biosynthesis | 6 | 2.40 | 5 | 0.06 | |||
Selenocompound metabolism | 8 | −1.03 | 5 | 1.29 | |||
Valine, leucine, and isoleucine degradation | 10 | −2.33 | 16 | −2.16 | |||
beta-Alanine metabolism | 6 | 0.71 | 11 | 0.75 | |||
Carb | Amino sugar and nucleotide sugar metabolism | 15 | −1.40 | 15 | −2.64 | 12 | 2.46 |
Phosphatidylinositol signaling system | 14 | −0.10 | 13 | 1.54 | 19 | −1.73 | |
Fructose and mannose metabolism | 10 | 0.31 | 12 | 0.19 | 8 | 2.85 | |
Starch and sucrose metabolism | 9 | −1.97 | 8 | −2.03 | 9 | −0.44 | |
Glyoxylate and dicarboxylate metabolism | 11 | −1.56 | 11 | −2.21 | 10 | −1.44 | |
Glycolysis/Gluconeogenesis | 18 | 0.18 | 18 | −2.22 | 13 | 1.17 | |
Pyruvate metabolism | 17 | −0.67 | 15 | −2.36 | 7 | 0.13 | |
Ascorbate and aldarate metabolism | 8 | −1.12 | 6 | −0.40 | |||
Propanoate metabolism | 7 | −1.52 | 9 | −1.39 | |||
Pentose phosphate pathway | 10 | −0.41 | 7 | 1.46 | |||
Nucleotide | Purine metabolism | 44 | 0.39 | 24 | 0.52 | 43 | 0.09 |
Pyrimidine metabolism | 29 | −0.57 | 15 | −0.15 | 24 | 0.08 |
10 h: APAP | 10 h: BB | 5 h: CCl4 | |||||
---|---|---|---|---|---|---|---|
Pathway | Metabolite | log(FC) | TIMBR Score | log(FC) | TIMBR Score | log(FC) | TIMBR Score |
Lipid | L-palmitoylcarnitine | 0.52 | 0.18 | 0.68 | 0.58 | 0.70 | 0.70 |
stearoyl sphingomyelin (d18:1/18:0) | 0.83 | 0.75 | 0.78 | 0.69 | 0.39 | 0.07 | |
sphingosine | 0.62 | 1.81 | 1.36 | 0.43 | 1.20 | 0.15 | |
sphingosine-1-phosphate | 0.37 | 1.73 | 0.41 | 0.43 | 0.32 | 0.02 | |
stearoylcarnitine | 0.46 | 0.27 | 0.83 | 0.61 | 0.45 | 0.75 | |
O-propanoylcarnitine | −0.69 | −0.32 | −0.27 | 0.61 | −0.54 | 0.73 | |
arachidonate | 0.51 | −0.29 | 0.34 | 0.54 | - | ||
cholesterol | 0.28 | 0.20 | 0.48 | −2.68 | |||
choline | 0.29 | 2.46 | 0.16 | 0.81 | |||
L-carnitine | −0.38 | −0.35 | −0.23 | 0.63 | |||
O-butanoylcarnitine | −0.60 | −0.24 | −0.40 | 0.61 | |||
chenodeoxycholic acid | −1.64 | −1.04 | −1.43 | −1.68 | |||
(R)-3-hydroxybutanoate | 1.50 | 0.47 | 0.77 | 0.95 | |||
16-hydroxyhexadecanoic acid | 0.45 | 0.46 | 0.56 | 0.81 | |||
3-hydroxyisobutyrate | 1.03 | 0.62 | 0.53 | 0.72 | |||
3-methyl-2-oxobutyrate | 0.30 | 0.61 | 0.29 | 0.69 | |||
sphinganine-1-phosphate | 1.32 | 0.46 | 0.79 | 0.04 | |||
L-oleoylcarnitine | 0.55 | 0.60 | 0.34 | 0.72 | |||
mead acid | 0.43 | −0.36 | 0.78 | −0.60 | |||
tauroursodeoxycholate | 0.55 | −1.30 | 0.97 | −1.96 | |||
Amino Acid | methylimidazoleacetic acid | −1.02 | −0.49 | −3.64 | 0.45 | −2.12 | 0.94 |
creatine | 0.43 | 1.35 | 0.38 | 0.70 | |||
GSSG | −1.15 | −0.60 | −0.58 | 0.53 | |||
aspartate | −0.38 | −0.49 | −0.17 | 0.48 | |||
citrulline | −0.20 | −0.67 | −0.29 | 0.63 | |||
cysteine | −0.56 | −0.53 | −0.47 | 0.62 | |||
guanidinoacetate | −0.79 | −0.39 | −0.45 | 0.36 | |||
ornithine | −0.64 | −0.79 | −0.23 | 0.62 | |||
arginine | −0.27 | 0.94 | −0.17 | 0.67 | |||
5-oxoproline | 0.24 | 0.53 | 0.23 | 1.34 | |||
glutamine | 0.14 | 0.51 | 0.24 | 1.15 | |||
serotonin | 3.31 | 0.58 | 2.21 | 0.62 | |||
urocanate | 0.40 | 0.43 | 1.23 | 0.85 | |||
kynurenine | −0.30 | 0.59 | −0.45 | 0.80 | |||
Carb | fructose | 0.53 | 0.36 | 0.56 | 0.55 | ||
D-glucitol | −2.47 | 0.61 | −2.32 | 0.69 | |||
Nucleo-tide | cytidine | 0.99 | 1.18 | 1.14 | 0.38 | 0.64 | −0.05 |
spermidine | 1.10 | 0.82 | 0.96 | 0.14 | |||
uracil | 0.51 | 0.42 | 0.41 | 0.55 | |||
thymidine | 0.33 | 0.36 | 0.31 | 0.14 | |||
urate | 0.38 | 0.80 | 0.34 | 0.01 | |||
uridine | 0.10 | 0.26 | 0.46 | 0.12 | |||
thymine | 0.33 | 0.46 | 0.61 | −0.30 | |||
Cofactor | 4-pyridoxate | 0.39 | −0.67 | 0.34 | 0.61 | 0.39 | 0.69 |
D-gluconic acid | 1.16 | 0.33 | 0.57 | 0.51 | |||
oxalate | 0.23 | 0.18 | 0.43 | 0.40 | |||
threonate | 0.42 | 0.00 | 0.58 | 0.35 |
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Pannala, V.R.; Estes, S.K.; Rahim, M.; Trenary, I.; O’Brien, T.P.; Shiota, C.; Printz, R.L.; Reifman, J.; Shiota, M.; Young, J.D.; et al. Toxicant-Induced Metabolic Alterations in Lipid and Amino Acid Pathways Are Predictive of Acute Liver Toxicity in Rats. Int. J. Mol. Sci. 2020, 21, 8250. https://doi.org/10.3390/ijms21218250
Pannala VR, Estes SK, Rahim M, Trenary I, O’Brien TP, Shiota C, Printz RL, Reifman J, Shiota M, Young JD, et al. Toxicant-Induced Metabolic Alterations in Lipid and Amino Acid Pathways Are Predictive of Acute Liver Toxicity in Rats. International Journal of Molecular Sciences. 2020; 21(21):8250. https://doi.org/10.3390/ijms21218250
Chicago/Turabian StylePannala, Venkat R., Shanea K. Estes, Mohsin Rahim, Irina Trenary, Tracy P. O’Brien, Chiyo Shiota, Richard L. Printz, Jaques Reifman, Masakazu Shiota, Jamey D. Young, and et al. 2020. "Toxicant-Induced Metabolic Alterations in Lipid and Amino Acid Pathways Are Predictive of Acute Liver Toxicity in Rats" International Journal of Molecular Sciences 21, no. 21: 8250. https://doi.org/10.3390/ijms21218250