Cargando…

Genome-Scale Metabolic Modeling Reveals Sequential Dysregulation of Glutathione Metabolism in Livers from Patients with Alcoholic Hepatitis

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 d...

Descripción completa

Detalles Bibliográficos
Autores principales: Manchel, Alexandra, Mahadevan, Radhakrishnan, Bataller, Ramon, Hoek, Jan B., Vadigepalli, Rajanikanth
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9788589/
https://www.ncbi.nlm.nih.gov/pubmed/36557195
http://dx.doi.org/10.3390/metabo12121157
_version_ 1784858790696321024
author Manchel, Alexandra
Mahadevan, Radhakrishnan
Bataller, Ramon
Hoek, Jan B.
Vadigepalli, Rajanikanth
author_facet Manchel, Alexandra
Mahadevan, Radhakrishnan
Bataller, Ramon
Hoek, Jan B.
Vadigepalli, Rajanikanth
author_sort Manchel, Alexandra
collection PubMed
description 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.
format Online
Article
Text
id pubmed-9788589
institution National Center for Biotechnology Information
language English
publishDate 2022
publisher MDPI
record_format MEDLINE/PubMed
spelling pubmed-97885892022-12-24 Genome-Scale Metabolic Modeling Reveals Sequential Dysregulation of Glutathione Metabolism in Livers from Patients with Alcoholic Hepatitis Manchel, Alexandra Mahadevan, Radhakrishnan Bataller, Ramon Hoek, Jan B. Vadigepalli, Rajanikanth Metabolites Article 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. MDPI 2022-11-22 /pmc/articles/PMC9788589/ /pubmed/36557195 http://dx.doi.org/10.3390/metabo12121157 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Manchel, Alexandra
Mahadevan, Radhakrishnan
Bataller, Ramon
Hoek, Jan B.
Vadigepalli, Rajanikanth
Genome-Scale Metabolic Modeling Reveals Sequential Dysregulation of Glutathione Metabolism in Livers from Patients with Alcoholic Hepatitis
title Genome-Scale Metabolic Modeling Reveals Sequential Dysregulation of Glutathione Metabolism in Livers from Patients with Alcoholic Hepatitis
title_full Genome-Scale Metabolic Modeling Reveals Sequential Dysregulation of Glutathione Metabolism in Livers from Patients with Alcoholic Hepatitis
title_fullStr Genome-Scale Metabolic Modeling Reveals Sequential Dysregulation of Glutathione Metabolism in Livers from Patients with Alcoholic Hepatitis
title_full_unstemmed Genome-Scale Metabolic Modeling Reveals Sequential Dysregulation of Glutathione Metabolism in Livers from Patients with Alcoholic Hepatitis
title_short Genome-Scale Metabolic Modeling Reveals Sequential Dysregulation of Glutathione Metabolism in Livers from Patients with Alcoholic Hepatitis
title_sort genome-scale metabolic modeling reveals sequential dysregulation of glutathione metabolism in livers from patients with alcoholic hepatitis
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9788589/
https://www.ncbi.nlm.nih.gov/pubmed/36557195
http://dx.doi.org/10.3390/metabo12121157
work_keys_str_mv AT manchelalexandra genomescalemetabolicmodelingrevealssequentialdysregulationofglutathionemetabolisminliversfrompatientswithalcoholichepatitis
AT mahadevanradhakrishnan genomescalemetabolicmodelingrevealssequentialdysregulationofglutathionemetabolisminliversfrompatientswithalcoholichepatitis
AT batallerramon genomescalemetabolicmodelingrevealssequentialdysregulationofglutathionemetabolisminliversfrompatientswithalcoholichepatitis
AT hoekjanb genomescalemetabolicmodelingrevealssequentialdysregulationofglutathionemetabolisminliversfrompatientswithalcoholichepatitis
AT vadigepallirajanikanth genomescalemetabolicmodelingrevealssequentialdysregulationofglutathionemetabolisminliversfrompatientswithalcoholichepatitis