HepatoNet1: a comprehensive metabolic reconstruction of the human hepatocyte for the analysis of liver physiology

Gille, Christoph; Bölling, Christian; Hoppe, Andreas; Bulik, Sascha; Hoffmann, Sabrina; Hübner, Katrin; Karlstädt, Anja; Ganeshan, Ramanan; König, Matthias; Rother, Kristian; Weidlich, Michael; Behre, Jörn; Holzhütter, Hermann−Georg

doi:10.1038/msb.2010.62

Cited by 256 publications

(306 citation statements)

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“…We first merged metabolism of lipids and lipoproteins in Reactome, a manually curated and peer-reviewed pathway database 61 , and the literature-based GEMs including Recon 1 (ref. 12), EHMN 13,14 and HepatoNet 1, a manually reconstructed GEM for hepatocytes 1 . Extensive lipid metabolism involving 59 different FAs in the comprehensive database for lipid biology for mammalian cells, Lipidomics Gateway 62 , were included in the network and the gaps in the resulting network were filled using public databases such as KEGG 60 and HumanCyc 63 .…”

Section: Methodsmentioning

confidence: 99%

“…GEMs provide biologically meaningful mechanistic basis for the genotype-phenotype relationships, yet it is necessary to have functional cell-type GEMs to identify the metabolic differences between different states. We reconstructed iHepatocytes2322 by merging recently generated GEM for hepatocytes iHepatocyte1154 and previously published liver models 1,15,21,22 . iHepatocyte1154 was generated from the HMR database using the INIT algorithm, which allows for automated reconstruction of GEMs based on the celltype-specific proteome in the HPA (http://www.proteinatlas.org) 20 .…”

Section: Methodsmentioning

confidence: 99%

“…In the model, 74% of the reactions are associated to one or more genes. iHepatocytes2322 was validated with 256 known biological functions of hepatocytes (Supplementary Data 5), based on the definitions by Gille et al 1 , by using the checkTasks function in the RAVEN Toolbox 23 .…”

Section: Methodsmentioning

confidence: 99%

“…H epatocytes have a wide range of physiological functions, including production of bile and hormones, removal of toxic substances, homeostatic regulation of the plasma constituents and synthesis of most plasma proteins 1 . The hepatocytes, the most metabolically active cell types in human, play a major role in overall human metabolism.…”

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confidence: 99%

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Genome-scale metabolic modelling of hepatocytes reveals serine deficiency in patients with non-alcoholic fatty liver disease

et al. 2014

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Several liver disorders result from perturbations in the metabolism of hepatocytes, and their underlying mechanisms can be outlined through the use of genome-scale metabolic models (GEMs). Here we reconstruct a consensus GEM for hepatocytes, which we call iHepatocytes2322, that extends previous models by including an extensive description of lipid metabolism. We build iHepatocytes2322 using Human Metabolic Reaction 2.0 database and proteomics data in Human Protein Atlas, which experimentally validates the incorporated reactions. The reconstruction process enables improved annotation of the proteomics data using the network centric view of iHepatocytes2322. We then use iHepatocytes2322 to analyse transcriptomics data obtained from patients with non-alcoholic fatty liver disease. We show that blood concentrations of chondroitin and heparan sulphates are suitable for diagnosing non-alcoholic steatohepatitis and for the staging of non-alcoholic fatty liver disease. Furthermore, we observe serine deficiency in patients with NASH and identify PSPH, SHMT1 and BCAT1 as potential therapeutic targets for the treatment of non-alcoholic steatohepatitis.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

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Genome-scale metabolic modelling of hepatocytes reveals serine deficiency in patients with non-alcoholic fatty liver disease

et al. 2014

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“…Liver toxicity (hepatotoxicity) is responsible for a high percentage of late-stage attrition in drug development and on-market withdrawals. [1][2] A number of liver models have been proposed, ranging from computational [3][4] , through liver slices 5 , to cultures of primary or secondary liver cells. 6 Cultured primary hepatocytes are currently seen as the gold-standard for drug testing, but it is acknowledged that they rapidly alter their phenotype in culture, meaning that screening assays must be carefully validated, and complicating extrapolation to in vivo.…”

Section: Introductionmentioning

confidence: 99%

Primary Liver Cells Cultured on Carbon Nanotube Substrates for Liver Tissue Engineering and Drug Discovery Applications

Abdullah

Azad

Ovalle‐Robles

et al. 2014

ACS Appl. Mater. Interfaces

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Here we explore the use of two-and three-dimensional scaffolds of multi-walled-carbon nanotubes (MWNTs) for hepatocyte cell culture. Our objective is to study the use of these scaffolds in liver tissue engineering and drug discovery. In our experiments, primary rat hepatocytes, the parenchymal (main functional) cell type in the liver, were cultured on aligned nanogrooved MWNT sheets, MWNT yarns, or standard 2-dimensional culture conditions as a control. We find comparable cell viability between all three culture conditions, but enhanced production of the hepatocyte-specific marker albumin for cells cultured on MWNTs. The basal activity of two clinically relevant cytochrome P450 enzymes, CYP1A2 and CYP3A4, are similar on all substrates, but we find enhanced induction of CYP1A2 for cells on the MWNT sheets. Our data thus supports the use of these substrates for applications including tissue engineering, enhancing liver-specific functions, as well an in vitro model systems with enhanced predictive capability in drug discovery and development.

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Integration of Metabolic Knowledge for Genome‐Scale Metabolic Reconstruction

Masoudi‐Nejad

Salehzadeh‐Yazdi

Akbari‐Birgani

et al. 2013

Biological Knowledge Discovery Handbook

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INTRODUCTIONGenome-scale metabolic reconstruction is the ultimate goal of system biologists for finding out the genotype-phenotype relationship. For achieving this purpose, we need enough knowledge about the metabolic pathways and genome annotation. During the present study, we aim to describe the foundational concepts, central to omics data, model formulation, history, method, and applications of metabolic network reconstruction as well as some related sources. In Section 45.2, we describe omics data and high-throughput technologies for gaining these data. In section 45.3, we present different ways for metabolic network modeling. In section 45.4, we summarize the history of genome-scale modeling as one of the most important methods for metabolic network modeling. In sections 45.5 and 45.6, we elucidate how genome-scale metabolic models could be generated and what their applications are. Finally, in section 45.7, we review biochemical pathways and genome annotation databases. OMICs ERAInnovative omics technologies such as genomics, transcriptomics, proteomics, and metabolomics facilitate a strategy toward the simultaneous analysis of the large number of genes, transcripts, proteins, and metabolites. Therefore, a huge volume of data has generated about the make-up of cells and their behavior at various cellular levels and different environmental conditions, which enable us to reconstruct genome-scale biomolecular networks (e.g., transcriptional regulatory networks, interactomic networks, and metabolic networks)Knowledge Discovery Handbook: Preprocessing, Mining, and Postprocessing of Biological Data, First Edition. Edited by Mourad Elloumi and Albert Y. Zomaya.

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HepatoNet1: a comprehensive metabolic reconstruction of the human hepatocyte for the analysis of liver physiology

Cited by 256 publications

References 54 publications

Genome-scale metabolic modelling of hepatocytes reveals serine deficiency in patients with non-alcoholic fatty liver disease

Genome-scale metabolic modelling of hepatocytes reveals serine deficiency in patients with non-alcoholic fatty liver disease

Primary Liver Cells Cultured on Carbon Nanotube Substrates for Liver Tissue Engineering and Drug Discovery Applications

Integration of Metabolic Knowledge for Genome‐Scale Metabolic Reconstruction

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