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Large-scale in silico modeling of metabolic interactions between cell types in the human brain.

Lewis NE, Schramm G, Bordbar A, Schellenberger J, Andersen MP, Cheng JK, Patel N, Yee A, Lewis RA, Eils R, König R, Palsson BØ - Nat. Biotechnol. (2010)

Bottom Line: Transport reactions are used to account for the transfer of metabolites between models of different cell types via the interstitial fluid.Analysis of the models identifies genes and pathways that may explain observed experimental phenomena, including the differential effects of the disease on cell types and regions of the brain.Constraint-based modeling can thus contribute to the study and analysis of multicellular metabolic processes in the human tissue microenvironment and provide detailed mechanistic insight into high-throughput data analysis.

View Article: PubMed Central - PubMed

Affiliation: Department of Bioengineering, University of California, San Diego, La Jolla, California, USA.

ABSTRACT
Metabolic interactions between multiple cell types are difficult to model using existing approaches. Here we present a workflow that integrates gene expression data, proteomics data and literature-based manual curation to model human metabolism within and between different types of cells. Transport reactions are used to account for the transfer of metabolites between models of different cell types via the interstitial fluid. We apply the method to create models of brain energy metabolism that recapitulate metabolic interactions between astrocytes and various neuron types relevant to Alzheimer's disease. Analysis of the models identifies genes and pathways that may explain observed experimental phenomena, including the differential effects of the disease on cell types and regions of the brain. Constraint-based modeling can thus contribute to the study and analysis of multicellular metabolic processes in the human tissue microenvironment and provide detailed mechanistic insight into high-throughput data analysis.

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Singular Value Decomposition (SVD) of feasible pathways elucidates potential pathways that allow for coupling of mitochondria acetyl-CoA metabolism and cytosolic acetylcholine production21,000 unique feasible reaction sets were computed, each showing transport of mitochondrial acetyl-CoA carbon to the cytosol in human metabolism. SVD of a matrix of all 21,000 pathways yielded 3 primary pathways that allow this coupling of mitochondrial metabolism to acetylcholine production, by carrying the acetyl-CoA carbon on (a) N-acetyl-L-apartate, (b) citrate, or (c) acetoacetate. As shown by the second singular vector, reactions in the pathway with citrate tend to be missing from pathways when the reactions for the acetoacetate pathway are included. The third singular vector shows a similar relationship of the N-acetyl-L-aspartate pathway. The omic data and known enzyme localization only support the usage of citrate and acetoacetate as potential carriers in neurons.
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Figure 5: Singular Value Decomposition (SVD) of feasible pathways elucidates potential pathways that allow for coupling of mitochondria acetyl-CoA metabolism and cytosolic acetylcholine production21,000 unique feasible reaction sets were computed, each showing transport of mitochondrial acetyl-CoA carbon to the cytosol in human metabolism. SVD of a matrix of all 21,000 pathways yielded 3 primary pathways that allow this coupling of mitochondrial metabolism to acetylcholine production, by carrying the acetyl-CoA carbon on (a) N-acetyl-L-apartate, (b) citrate, or (c) acetoacetate. As shown by the second singular vector, reactions in the pathway with citrate tend to be missing from pathways when the reactions for the acetoacetate pathway are included. The third singular vector shows a similar relationship of the N-acetyl-L-aspartate pathway. The omic data and known enzyme localization only support the usage of citrate and acetoacetate as potential carriers in neurons.

Mentions: The first singular vector is dominated by reactions that occur most frequently in the reaction sets (e.g., water transport across the cell membrane). However, the second and third singular vectors are dominated by reaction sets that usually co-occur or never co-occur (Fig. 5). These reactions cluster into three distinct pathways, providing hypotheses to aid in the reconstruction process. The omic data used in the reconstruction process, and a thorough literature search eliminated the pathway using cytosolic acetyl-CoA sythetase (Fig. 5.a), and validated the other two, involving the transport and metabolism of acetyl-CoA-derived citrate or acetoacetate, using ATP-citrate lyase (ACITL) or cytosolic acetyl-CoA C-acetyltransferase (ACACT1r), respectively (Fig. 5.b–c; see Supplementary Notes for details).


Large-scale in silico modeling of metabolic interactions between cell types in the human brain.

Lewis NE, Schramm G, Bordbar A, Schellenberger J, Andersen MP, Cheng JK, Patel N, Yee A, Lewis RA, Eils R, König R, Palsson BØ - Nat. Biotechnol. (2010)

Singular Value Decomposition (SVD) of feasible pathways elucidates potential pathways that allow for coupling of mitochondria acetyl-CoA metabolism and cytosolic acetylcholine production21,000 unique feasible reaction sets were computed, each showing transport of mitochondrial acetyl-CoA carbon to the cytosol in human metabolism. SVD of a matrix of all 21,000 pathways yielded 3 primary pathways that allow this coupling of mitochondrial metabolism to acetylcholine production, by carrying the acetyl-CoA carbon on (a) N-acetyl-L-apartate, (b) citrate, or (c) acetoacetate. As shown by the second singular vector, reactions in the pathway with citrate tend to be missing from pathways when the reactions for the acetoacetate pathway are included. The third singular vector shows a similar relationship of the N-acetyl-L-aspartate pathway. The omic data and known enzyme localization only support the usage of citrate and acetoacetate as potential carriers in neurons.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3140076&req=5

Figure 5: Singular Value Decomposition (SVD) of feasible pathways elucidates potential pathways that allow for coupling of mitochondria acetyl-CoA metabolism and cytosolic acetylcholine production21,000 unique feasible reaction sets were computed, each showing transport of mitochondrial acetyl-CoA carbon to the cytosol in human metabolism. SVD of a matrix of all 21,000 pathways yielded 3 primary pathways that allow this coupling of mitochondrial metabolism to acetylcholine production, by carrying the acetyl-CoA carbon on (a) N-acetyl-L-apartate, (b) citrate, or (c) acetoacetate. As shown by the second singular vector, reactions in the pathway with citrate tend to be missing from pathways when the reactions for the acetoacetate pathway are included. The third singular vector shows a similar relationship of the N-acetyl-L-aspartate pathway. The omic data and known enzyme localization only support the usage of citrate and acetoacetate as potential carriers in neurons.
Mentions: The first singular vector is dominated by reactions that occur most frequently in the reaction sets (e.g., water transport across the cell membrane). However, the second and third singular vectors are dominated by reaction sets that usually co-occur or never co-occur (Fig. 5). These reactions cluster into three distinct pathways, providing hypotheses to aid in the reconstruction process. The omic data used in the reconstruction process, and a thorough literature search eliminated the pathway using cytosolic acetyl-CoA sythetase (Fig. 5.a), and validated the other two, involving the transport and metabolism of acetyl-CoA-derived citrate or acetoacetate, using ATP-citrate lyase (ACITL) or cytosolic acetyl-CoA C-acetyltransferase (ACACT1r), respectively (Fig. 5.b–c; see Supplementary Notes for details).

Bottom Line: Transport reactions are used to account for the transfer of metabolites between models of different cell types via the interstitial fluid.Analysis of the models identifies genes and pathways that may explain observed experimental phenomena, including the differential effects of the disease on cell types and regions of the brain.Constraint-based modeling can thus contribute to the study and analysis of multicellular metabolic processes in the human tissue microenvironment and provide detailed mechanistic insight into high-throughput data analysis.

View Article: PubMed Central - PubMed

Affiliation: Department of Bioengineering, University of California, San Diego, La Jolla, California, USA.

ABSTRACT
Metabolic interactions between multiple cell types are difficult to model using existing approaches. Here we present a workflow that integrates gene expression data, proteomics data and literature-based manual curation to model human metabolism within and between different types of cells. Transport reactions are used to account for the transfer of metabolites between models of different cell types via the interstitial fluid. We apply the method to create models of brain energy metabolism that recapitulate metabolic interactions between astrocytes and various neuron types relevant to Alzheimer's disease. Analysis of the models identifies genes and pathways that may explain observed experimental phenomena, including the differential effects of the disease on cell types and regions of the brain. Constraint-based modeling can thus contribute to the study and analysis of multicellular metabolic processes in the human tissue microenvironment and provide detailed mechanistic insight into high-throughput data analysis.

Show MeSH
Related in: MedlinePlus