Frontiers in Metabolic Flux Analysis on Human Disease

A special issue of Metabolites (ISSN 2218-1989). This special issue belongs to the section "Bioinformatics and Data Analysis".

Deadline for manuscript submissions: closed (15 October 2022) | Viewed by 6746

Special Issue Editor


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Guest Editor
Department of Medicine, Rutgers Robert Wood Johnson Medical School, Rutgers University, New Brunswick, NJ 08901, USA
Interests: metabolomics; mass spectrometry; stable isotope tracing; enzymology

Special Issue Information

Dear Colleagues,

Many human diseases are caused by a dysregulated metabolism. In addition to the measurements of metabolite abundance using metabolomic approaches, the characterization of dynamic metabolite interconversions, e.g., metabolic fluxes, offers mechanistic insight into the underlying pathology. A metabolic flux is defined as the rate of metabolite production or consumption. With a few exceptions, metabolic fluxes are not directly measurable. Instead, they have to be inferred from isotope tracing experiments and/or constraint-based models. These tools, which were originally developed for metabolic engineering purposes, have been applied to investigate human diseases such as inborn errors of metabolism, the metabolic vulnerability of cancer cells, cardiovascular diseases, and metabolic syndrome. These systematic understandings of human diseases hold promise for providing new diagnoses and treatments.

This Special Issue of Metabolites, “Frontiers in Metabolic Flux Analysis on Human Disease”, is dedicated to covering recent theoretical and application works pertinent to metabolic flux analysis and human diseases. We welcome studies ranging from cultured human cell systems to whole-body metabolism. New tracer strategies, computational tools, and analysis approaches are of particular interest.

Dr. Xiaoyang Su
Guest Editor

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Keywords

  • metabolic network modeling
  • metabolic flux analysis
  • flux balance analysis
  • isotope tracing
  • human metabolomics
  • whole-body metabolism

Published Papers (3 papers)

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Research

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20 pages, 7282 KiB  
Article
Genome-Scale Metabolic Modeling Reveals Sequential Dysregulation of Glutathione Metabolism in Livers from Patients with Alcoholic Hepatitis
by Alexandra Manchel, Radhakrishnan Mahadevan, Ramon Bataller, Jan B. Hoek and Rajanikanth Vadigepalli
Metabolites 2022, 12(12), 1157; https://doi.org/10.3390/metabo12121157 - 22 Nov 2022
Cited by 2 | Viewed by 2002
Abstract
Alcoholic hepatitis (AH) is the most severe form of alcoholic liver disease for which there is no efficacious treatment aiding most patients. AH manifests differently in individuals, with some patients showing debilitating symptoms more so than others. Previous studies showed significant metabolic dysregulation [...] Read more.
Alcoholic hepatitis (AH) is the most severe form of alcoholic liver disease for which there is no efficacious treatment aiding most patients. AH manifests differently in individuals, with some patients showing debilitating symptoms more so than others. Previous studies showed significant metabolic dysregulation associated with AH. Therefore, we sought to analyze how the activity of metabolic pathways differed in the liver of patients with varying degrees of AH severity. We utilized a genome-scale metabolic modeling approach that allowed for integration of a generic human cellular metabolic model with specific RNA-seq data corresponding to healthy and multiple liver disease states to predict the metabolic fluxes within each disease state. Additionally, we performed a systems-level analysis of the transcriptomic data and predicted metabolic flux data to identify the regulatory and functional differences in liver metabolism with increasing severity of AH. Our results provide unique insights into the sequential dysregulation of the solute transport mechanisms underlying the glutathione metabolic pathway with increasing AH disease severity. We propose targeting of the solute transporters in the glutathione pathway to mimic the flux activity of the healthy liver state as a potential therapeutic intervention for AH. Full article
(This article belongs to the Special Issue Frontiers in Metabolic Flux Analysis on Human Disease)
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10 pages, 1699 KiB  
Article
Differential Metabolism of Glycerol Based on Oral versus Intravenous Administration in Humans
by Ankit Shah, Yujue Wang and Fredric E. Wondisford
Metabolites 2022, 12(10), 890; https://doi.org/10.3390/metabo12100890 - 22 Sep 2022
Cited by 1 | Viewed by 1579
Abstract
Glycerol can be metabolized to glucose via gluconeogenesis or lactate via glycolysis. It is unknown if glycerol is metabolized similarly in the portal and systemic circulations in humans. Eight metabolically healthy overnight-fasted individuals received equimolar amounts of 13C3-glycerol orally and [...] Read more.
Glycerol can be metabolized to glucose via gluconeogenesis or lactate via glycolysis. It is unknown if glycerol is metabolized similarly in the portal and systemic circulations in humans. Eight metabolically healthy overnight-fasted individuals received equimolar amounts of 13C3-glycerol orally and intravenously on two separate occasions with serial blood draws over four hours. Serum samples underwent liquid chromatography–mass spectrometry analysis. Oral 13C3-glycerol administration led to higher average serum glucose enrichment than intravenous administration (5.02 ± 1.43 versus 4.07 ± 0.79%, p = 0.009). In contrast, intravenous 13C3-glycerol administration yielded higher average serum lactate enrichment than oral administration (5.67 ± 0.80 versus 4.85 ± 1.30%, p = 0.032). Peak serum glucose enrichment was also higher with oral administration (9.37 ± 2.93 versus 7.12 ± 1.28%, p = 0.010). Glycerol metabolism across the portal and systemic circulations is not congruent. Orally administered labeled glycerol led to greater labeled glucose production, while intravenously administration yielded greater lactate production. These data support direct glycerol to lactate conversion in humans. Full article
(This article belongs to the Special Issue Frontiers in Metabolic Flux Analysis on Human Disease)
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Review

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29 pages, 2666 KiB  
Review
Isotope-Assisted Metabolic Flux Analysis: A Powerful Technique to Gain New Insights into the Human Metabolome in Health and Disease
by Bilal Moiz, Andrew Li, Surya Padmanabhan, Ganesh Sriram and Alisa Morss Clyne
Metabolites 2022, 12(11), 1066; https://doi.org/10.3390/metabo12111066 - 4 Nov 2022
Cited by 7 | Viewed by 2385
Abstract
Cell metabolism represents the coordinated changes in genes, proteins, and metabolites that occur in health and disease. The metabolic fluxome, which includes both intracellular and extracellular metabolic reaction rates (fluxes), therefore provides a powerful, integrated description of cellular phenotype. However, intracellular fluxes cannot [...] Read more.
Cell metabolism represents the coordinated changes in genes, proteins, and metabolites that occur in health and disease. The metabolic fluxome, which includes both intracellular and extracellular metabolic reaction rates (fluxes), therefore provides a powerful, integrated description of cellular phenotype. However, intracellular fluxes cannot be directly measured. Instead, flux quantification requires sophisticated mathematical and computational analysis of data from isotope labeling experiments. In this review, we describe isotope-assisted metabolic flux analysis (iMFA), a rigorous computational approach to fluxome quantification that integrates metabolic network models and experimental data to generate quantitative metabolic flux maps. We highlight practical considerations for implementing iMFA in mammalian models, as well as iMFA applications in in vitro and in vivo studies of physiology and disease. Finally, we identify promising new frontiers in iMFA which may enable us to fully unlock the potential of iMFA in biomedical research. Full article
(This article belongs to the Special Issue Frontiers in Metabolic Flux Analysis on Human Disease)
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