Toxicant-Induced Metabolic Alterations in Lipid and Amino Acid Pathways Are Predictive of Acute Liver Toxicity in Rats

Liver disease and disorders associated with aberrant hepatocyte metabolism can be initiated via drug and environmental toxicant exposures. In this study, we tested the hypothesis that gene and metabolic profiling can reveal commonalities in liver response to different toxicants and provide the capability to identify early signatures of acute liver toxicity. We used Sprague Dawley rats and three classical hepatotoxicants: acetaminophen (2 g/kg), bromobenzene (0.4 g/kg), and carbon tetrachloride (0.3 g/kg), to identify early perturbations in liver metabolism after a single acute exposure dose. We measured changes in liver genes and plasma metabolites at two time points (5 and 10 h) and used genome-scale metabolic models to identify commonalities in liver responses across the three toxicants. We found strong correlations for gene and metabolic profiles between the toxicants, indicative of similarities in the liver response to toxicity. We identified several injury-specific pathways in lipid and amino acid metabolism that changed similarly across the three toxicants. Our findings suggest that several plasma metabolites in lipid and amino acid metabolism are strongly associated with the progression of liver toxicity, and as such, could be targeted and clinically assessed for their potential as early predictors of acute liver toxicity.

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Fibroblast‐specific genome‐scale modelling predicts an imbalance in amino acid metabolism in Refsum disease

FEBS Journal ◽

10.1111/febs.15292 ◽

2020 ◽

Vol 287 (23) ◽

pp. 5096-5113 ◽

Cited By ~ 1

Author(s):

Agnieszka B. Wegrzyn ◽

Katharina Herzog ◽

Albert Gerding ◽

Marcel Kwiatkowski ◽

Justina C. Wolters ◽

...

Keyword(s):

Amino Acid ◽

Amino Acid Metabolism ◽

Acid Metabolism ◽

Refsum Disease ◽

Scale Modelling ◽

Genome Scale

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Fibroblast-specific genome-scale modelling predicts an imbalance in amino acid metabolism in Refsum disease

10.1101/776575 ◽

2019 ◽

Author(s):

Agnieszka B. Wegrzyn ◽

Katharina Herzog ◽

Albert Gerding ◽

Marcel Kwiatkowski ◽

Justina C. Wolters ◽

...

Keyword(s):

Amino Acid ◽

Phytanic Acid ◽

Amino Acid Metabolism ◽

Acid Metabolism ◽

Disease Patient ◽

Metabolic Phenotype ◽

Scale Model ◽

Refsum Disease ◽

Model Based ◽

Genome Scale

ABSTRACTRefsum disease is an inborn error of metabolism that is characterised by a defect in peroxisomal α-oxidation of the branched-chain fatty acid phytanic acid. The disorder presents with late-onset progressive retinitis pigmentosa and polyneuropathy and can be diagnosed biochemically by elevated levels of phytanic acid in plasma and tissues of patients. To date, no cure exists for Refsum disease, but phytanic acid levels in patients can be reduced by plasmapheresis and a strict diet.In this study, we reconstructed a fibroblast-specific genome-scale model based on the recently published, FAD-curated model, based on Recon3D reconstruction. We used transcriptomics (available via GEO database with identifier GSE138379), metabolomics, and proteomics data (available via ProteomeXchange with identifier PXD015518), which we obtained from healthy controls and Refsum disease patient fibroblasts incubated with phytol, a precursor of phytanic acid.Our model correctly represents the metabolism of phytanic acid and displays fibroblast-specific metabolic functions. Using this model, we investigated the metabolic phenotype of Refsum disease at the genome-scale, and we studied the effect of phytanic acid on cell metabolism. We identified 53 metabolites that were predicted to discriminate between Healthy and Refsum disease patients, several of which with a link to amino acid metabolism. Ultimately, these insights in metabolic changes may provide leads for pathophysiology and therapy.

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Analysis of the cyanobacterial amino acid metabolism with a precise genome-scale metabolic reconstruction of Anabaena sp. UTEX 2576

Biochemical Engineering Journal ◽

10.1016/j.bej.2021.108008 ◽

2021 ◽

pp. 108008

Author(s):

Daniel A. Norena-Caro ◽

Cristal Zuniga ◽

Amber J. Pete ◽

Sven A. Saemundsson ◽

Morgan R. Donaldson ◽

...

Keyword(s):

Amino Acid ◽

Amino Acid Metabolism ◽

Acid Metabolism ◽

Metabolic Reconstruction ◽

Anabaena Sp ◽

Genome Scale

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Associations of network-derived metabolite clusters with prevalent type 2 diabetes among adults of Puerto Rican descent

BMJ Open Diabetes Research & Care ◽

10.1136/bmjdrc-2021-002298 ◽

2021 ◽

Vol 9 (1) ◽

pp. e002298

Author(s):

Danielle E Haslam ◽

Liming Liang ◽

Dong D Wang ◽

Rachel S Kelly ◽

Clemens Wittenbecher ◽

...

Keyword(s):

Type 2 Diabetes ◽

Amino Acid ◽

Puerto Rican ◽

Amino Acid Metabolism ◽

Acid Metabolism ◽

Meta Analysis ◽

Random Effect ◽

Plasma Metabolites ◽

Blood Draw

IntroductionWe investigated whether network analysis revealed clusters of coregulated metabolites associated with prevalent type 2 diabetes (T2D) among Puerto Rican adults.Research design and methodsWe used liquid chromatography-mass spectrometry to measure fasting plasma metabolites (>600) among participants aged 40–75 years in the Boston Puerto Rican Health Study (BPRHS; discovery) and San Juan Overweight Adult Longitudinal Study (SOALS; replication), with (n=357; n=77) and without (n=322; n=934) T2D, respectively. Among BPRHS participants, we used unsupervised partial correlation network-based methods to identify and calculate metabolite cluster scores. Logistic regression was used to assess cross-sectional associations between metabolite clusters and prevalent T2D at the baseline blood draw in the BPRHS, and significant associations were replicated in SOALS. Inverse-variance weighted random-effect meta-analysis was used to combine cohort-specific estimates.ResultsSix metabolite clusters were significantly associated with prevalent T2D in the BPRHS and replicated in SOALS (false discovery rate (FDR) <0.05). In a meta-analysis of the two cohorts, the OR and 95% CI (per 1 SD increase in cluster score) for prevalent T2D were as follows for clusters characterized primarily by glucose transport (0.21 (0.16 to 0.30); FDR <0.0001), sphingolipids (0.40 (0.29 to 0.53); FDR <0.0001), acyl cholines (0.35 (0.22 to 0.56); FDR <0.0001), sugar metabolism (2.28 (1.68 to 3.09); FDR <0.0001), branched-chain and aromatic amino acids (2.22 (1.60 to 3.08); FDR <0.0001), and fatty acid biosynthesis (1.54 (1.29 to 1.85); FDR <0.0001). Three additional clusters characterized by amino acid metabolism, cell membrane components, and aromatic amino acid metabolism displayed significant associations with prevalent T2D in the BPRHS, but these associations were not replicated in SOALS.ConclusionsAmong Puerto Rican adults, we identified several known and novel metabolite clusters that associated with prevalent T2D.

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Influence of Liver Condition and Copper on Selective Parameters of Post-Mortem Dog Tissue Samples

Animals ◽

10.3390/ani8120237 ◽

2018 ◽

Vol 8 (12) ◽

pp. 237

Author(s):

Isabella Corsato Alvarenga ◽

Charles Aldrich ◽

Dennis Jewell

Keyword(s):

Amino Acid ◽

Amino Acid Metabolism ◽

Acid Metabolism ◽

Octadecadienoic Acid ◽

Complete Blood Count ◽

Plasma Metabolites ◽

Hepatic Tissue ◽

Post Mortem ◽

Hepatic Copper ◽

Microscopic Evaluation

One of the liver functions is copper storage, which can be toxic when in excess. The objective of this retrospective study was to determine the relationship between hepatic copper and pathology conditions in stored samples from 55 post-mortem dogs (37 Beagles, 12 Labrador Retrievers, and 6 Labrador Mixes). The analyses evaluated data from blood chemistry and complete blood count (CBC) that were measured immediately before euthanasia, and liver biopsies which were harvested at necropsy and frozen at −80 °C. Slides for microscopic evaluation were prepared, and liver copper and plasma metabolites were measured. Hepatic copper was correlated (p ≤ 0.001) with monoacylglycerols, 13-HODE + 9-HODE (13-hydroxy-9,11-octadecadienoic acid + 9-hydroxy-10,12-octadecadienoic acid), and stearoyl-arachidonoyl-glycerophosphocholine. This indicates lipid metabolism modification and cell membrane oxidation. However, hepatic copper was not related to liver histopathology severity or altered liver biomarkers. The severity of liver pathology was positively correlated (p ≤ 0.05) with liver enzymes, bile salts, and glycerophosphocholines, suggesting cholestasis and altered lipid and amino acid metabolism. Liver neoplasia had increased (p ≤ 0.05) metabolites derived from nucleotides, along with an increase (p ≤ 0.05) in α-ketoglutarate from the energy and amino acid metabolism (p ≤ 0.05), suggesting rapid cell division. This study offers further insight regarding changes in metabolism due to hepatic tissue damage.

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The biochemical and metabolic profiles of dairy cows with mycotoxins-contaminated diets

PeerJ ◽

10.7717/peerj.8742 ◽

2020 ◽

Vol 8 ◽

pp. e8742

Author(s):

Qian Wang ◽

Yangdong Zhang ◽

Nan Zheng ◽

Shengguo Zhao ◽

Songli Li ◽

...

Keyword(s):

Amino Acid ◽

Dairy Cows ◽

Amino Acid Metabolism ◽

Acid Metabolism ◽

Plasma Metabolites ◽

Control Group ◽

Treatment Groups ◽

Total Antioxidant ◽

Biochemical Profiles ◽

Biochemical Analyses

Background Previous studies on the effects of mycotoxins have solely focused on their biochemical profiles or products in dairy ruminants. Changes in metabolism that occur after exposure to mycotoxins, as well as biochemical changes, have not been explored. Methods We measured the biochemical and metabolic changes in dairy cows after exposure to mycotoxins using biochemical analyses and nuclear magnetic resonance. Twenty-four dairy cows were randomly assigned to three different treatment groups. Control cows received diets with 2 kg uncontaminated cottonseed. Cows in the 50% replacement group received the same diet as the control group, but with 1 kg of uncontaminated cottonseed and 1 kg of cottonseed contaminated with mycotoxins. Cows in the 100% replacement group received the same diet as the control, but with 2 kg contaminated cottonseed. Results The results showed that serum γ-glutamyl transpeptidase and total antioxidant capacities were significantly affected by cottonseed contaminated with mycotoxins. There were also significant differences in isovalerate and NH3-N levels, and significant differences in the eight plasma metabolites among the three groups. These metabolites are mainly involved in amino acid metabolism pathways. Therefore, the results suggest that amino acid metabolism pathways may be affected by mycotoxins exposure.

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