Detailed insights into the biological functions of the liver and an understanding of its crosstalk with other human tissues and the gut microbiota can be used to develop novel strategies for the prevention and treatment of liver-associated diseases, including fatty liver disease, cirrhosis, hepatocellular carcinoma and type 2 diabetes mellitus. Biological network models, including metabolic, transcriptional regulatory, protein–protein interaction, signalling and co-expression networks, can provide a scaffold for studying the biological pathways operating in the liver in connection with disease development in a systematic manner. Here, we review studies in which biological network models were used to integrate multiomics data to advance our understanding of the pathophysiological responses of complex liver diseases. We also discuss how this mechanistic approach can contribute to the discovery of potential biomarkers and novel drug targets, which might lead to the design of targeted and improved treatment strategies. Finally, we present a roadmap for the successful integration of models of the liver and other human tissues with the gut microbiota to simulate whole-body metabolic functions in health and disease.
Detailed characterization of human liver tissue and gut microbiota is enabled by omics technologies.
Biological network models are functional tools for the exploration and integration of multiomics data.
Systems biology uses a holistic and integrative approach for comprehensive analysis of the biological functions in healthy and diseased states.
Systems biology approaches have been successfully employed in gastroenterology and hepatology to identify biomarkers and drug targets.
These integrative tools can be used for simulation of liver tissue functions and crosstalk of liver with other tissues.
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Funding was provided by the Knut and Alice Wallenberg Foundation. The research leading to these results has received support from the Innovative Medicines Initiative Joint Undertaking under European Medical Information Framework grant agreement no. 115372.
A.M., M.U. and J.B. are founders of ScandiBio and ScandiEdge Therapeutics.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
TCSBN: a database of tissue and cancer-specific biological networks: http://inetmodels.com/
A field that analyses data to quantify protein abundance.
A field that measures mRNA transcript levels.
A field that analyses data to determine the abundance of small cellular metabolites.
A field that directly analyses the genomes contained within an environmental sample.
A field that quantifies the flux of substrates through a reaction step to establish dynamic changes of molecules within a cell over time.
A field that analyses the interactions between major constituents of cells, including proteins and metabolites, to resolve the whole set of molecular interactions in cells.
- Systems biology
An interdisciplinary field that studies the complex interactions within cells and/or tissues using a holistic approach.
- Biological networks
Models that make up the basis of systems biology and provide a mathematical representation of connections between the constituents of cells or tissues.
- Genome-scale metabolic models
Mathematical models for a collection of metabolic biochemical reactions and the associated enzymes and transporters.
- Gene regulatory networks
Networks that represent the interactions between transcription factors and their target genes.
- Protein–protein interaction networks
Networks that provides detailed information about the protein complexes formed by biochemical events.
- Signalling networks
Networks describing sequential molecular reactions that govern how a cell responds to its environment.
- Gene co-expression networks
Networks representing the links between the expression of genes that might result in functional connections.
A collection of cell components secreted to the outside of the cell or tissue.
- Druggable proteome
A collection of the proteins used in the development of drugs.
- Network topology
The arrangement of the network components including links, nodes and edges.
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Mardinoglu, A., Boren, J., Smith, U. et al. Systems biology in hepatology: approaches and applications. Nat Rev Gastroenterol Hepatol 15, 365–377 (2018). https://doi.org/10.1038/s41575-018-0007-8
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