Abstract
Alcoholic liver disease (ALD) is a complex disease characterized by damages to the liver and is the consequence of excessive alcohol consumption over years. Since this disease is associated with several pathway failures, pathway reconstruction and network analysis are likely to explicit the molecular basis of the disease. To this aim, in this paper, a network medicine approach was employed to integrate interactome (protein–protein interaction and signaling pathways) and transcriptome data to reconstruct both a static network of ALD and a dynamic model for it. Several data sources were exploited to assemble a set of ALD-associated genes which further was used for network reconstruction. Moreover, a comprehensive literature mining reveals that there are four signaling pathways with crosstalk (TLR4, NF- \(\upkappa \)B, MAPK and Apoptosis) which play a major role in ALD. These four pathways were exploited to reconstruct a dynamic model of ALD. The results assure that these two models are consistent with a number of experimental observations. The static network of ALD and its dynamic model are the first models provided for ALD which offer potentially valuable information for researchers in this field.
Similar content being viewed by others
References
Affò S, Dominguez M, Lozano JJ, Sancho-Bru P, Rodrigo-Torres D, Morales-Ibanez O et al (2013) Transcriptome analysis identifies TNF superfamily receptors as potential therapeutic targets in alcoholic hepatitis. Gut 62:452–460
Aroor AR, Shukla SD (2004) MAP kinase signaling in diverse effects of ethanol. Life Sci 74:2339–2364
Bader GD, Cary MP, Sander C (2006) Pathguide: a pathway resource list. Nucleic Acids Res 34:D504–D506
Barrett T, Edgar R (2006) [19] Gene expression omnibus: microarray data storage, submission, retrieval, and analysis. Methods Enzymol 411:352–369
Berger B, Peng J, Singh M (2013) Computational solutions for omics data. Nat Rev Genet 14:333–346
Bindea G, Mlecnik B, Hackl H, Charoentong P, Tosolini M, Kirilovsky A et al (2009) ClueGO: a Cytoscape plug-in to decipher functionally grouped gene ontology and pathway annotation networks. Bioinformatics 25:1091–1093
Chatr-Aryamontri A, Breitkreutz B-J, Heinicke S, Boucher L, Winter A, Stark C et al (2013) The BioGRID interaction database: 2013 update. Nucleic Acids Res 41:D816–D823
Chen EY, Xu H, Gordonov S, Lim MP, Perkins MH, Ma’ayan A (2012) Expression2Kinases: mRNA profiling linked to multiple upstream regulatory layers. Bioinformatics 28:105–111
Cline MS, Smoot M, Cerami E, Kuchinsky A, Landys N, Workman C et al (2007) Integration of biological networks and gene expression data using Cytoscape. Nat Protoc 2:2366–2382
Covert MW, Leung TH, Gaston JE, Baltimore D (2005) Achieving stability of lipopolysaccharide-induced NF-\(\upkappa \)B activation. Science 309:1854–1857
Darnell JE Jr, Kerr IM, Stark GR (1994) Jak-STAT pathways and transcriptional activation in response to IFNs and other extracellular signaling proteins. Sci AAAS Wkly Paper Edit Incl Guide Sci Inf 264:1415–1420
Fischer HP (2008) Mathematical modeling of complex biological systems: from parts lists to understanding systems behavior. Alcohol Res Health 31:49
Funahashi A, Matsuoka Y, Jouraku A, Morohashi M, Kikuchi N, Kitano H (2008) CellDesigner 3.5: a versatile modeling tool for biochemical networks. IEEE Proc 96:1254–1265
Gao B, Bataller R (2011) Alcoholic liver disease: pathogenesis and new therapeutic targets. Gastroenterology 141:1572–1585
Ghosh S (1999) Regulation of inducible gene expression by the transcription factor NF-\(\upkappa \)B. Immunol Res 19:183–190
Hornberg JJ, Bruggeman FJ, Westerhoff HV, Lankelma J (2006) Cancer: a systems biology disease. Biosystems 83:81–90
Hritz I, Mandrekar P, Velayudham A, Catalano D, Dolganiuc A, Kodys K et al (2008) The critical role of toll-like receptor (TLR) 4 in alcoholic liver disease is independent of the common TLR adapter MyD88. Hepatology 48:1224–1231
Ji ZL, Chen X, Zhen C, Yao L, Han L, Yeo W et al (2003) KDBI: kinetic data of bio-molecular interactions database. Nucleic Acids Res 31:255–257
Joshi-Tope G, Gillespie M, Vastrik I, D’Eustachio P, Schmidt E, de Bono B et al (2005) Reactome: a knowledgebase of biological pathways. Nucleic Acids Res 33:D428–D432
Kandasamy K, Mohan SS, Raju R, Keerthikumar S, Kumar GSS, Venugopal AK et al (2010) NetPath: a public resource of curated signal transduction pathways. Genome Biol 11:1
Kanehisa M, Goto S (2000) KEGG: kyoto encyclopedia of genes and genomes. Nucleic Acids Res 28:27–30
Kawai T, Akira S (2006) TLR signaling. Cell Death Differ 13:816–825
Kawai T, Adachi O, Ogawa T, Takeda K, Akira S (1999) Unresponsiveness of MyD88-deficient mice to endotoxin. Immunity 11:115–122
Kawai T, Takeuchi O, Fujita T, Inoue J-I, Mühlradt PF, Sato S et al (2001) Lipopolysaccharide stimulates the MyD88-independent pathway and results in activation of IFN-regulatory factor 3 and the expression of a subset of lipopolysaccharide-inducible genes. J Immunol 167:5887–5894
Kerr IM, Costa-Pereira AP, Lillemeier BF, Strobl B (2003) Of JAKs, STATs, blind watchmakers, jeeps and trains. FEBS Lett 546:1–5
Kishore R, Hill JR, McMullen MR, Frenkel J, Nagy LE (2002) ERK1/2 and Egr-1 contribute to increased TNF-\(\upalpha \) production in rat Kupffer cells after chronic ethanol feeding,”. Am J Physiol Gastrointest Liver Physiol 282:G6–G15
Kisseleva T, Bhattacharya S, Braunstein J, Schindler C (2002) Signaling through the JAK/STAT pathway, recent advances and future challenges. Gene 285:1–24
Lambert JD (1973) Computational methods in ordinary differential equations
Le Novere N, Bornstein B, Broicher A, Courtot M, Donizelli M, Dharuri H et al (2006) BioModels Database: a free, centralized database of curated, published, quantitative kinetic models of biochemical and cellular systems. Nucleic Acids Res 34:D689–D691
Lin C-P, Liu C-R, Lee C-N, Chan T-S, Liu HE (2010) Targeting c-Myc as a novel approach for hepatocellular carcinoma. World J Hepatol 2:16
Loscalzo J, Barabasi AL (2011) Systems biology and the future of medicine. Wiley Interdiscip Rev Syst Biol Med 3:619–627
Louvet A, Mathurin P (2015) Alcoholic liver disease: mechanisms of injury and targeted treatment. Nat Rev Gastroenterol Hepatol 12:231–242
Mahtani KR, Brook M, Dean JL, Sully G, Saklatvala J, Clark AR (2001) Mitogen-activated protein kinase p38 controls the expression and posttranslational modification of tristetraprolin, a regulator of tumor necrosis factor alpha mRNA stability. Mol Cell Biol 21:6461–6469
Mandrekar P, Szabo G (2009) Signalling pathways in alcohol-induced liver inflammation. J Hepatol 50:1258–1266
Mandrekar P, Ambade A (2012) Cellular signaling pathways in alcoholic liver disease
Martinez A, Castro A, Dorronsoro I, Alonso M (2002) Glycogen synthase kinase 3 (GSK-3) inhibitors as new promising drugs for diabetes, neurodegeneration, cancer, and inflammation. Med Res Rev 22:373–384
Materi W, Wishart DS (2007) Computational systems biology in drug discovery and development: methods and applications. Drug Discov Today 12:295–303
Mattingly C, Rosenstein M, Colby G, Forrest J Jr, Boyer J (2006) The comparative toxicogenomics database (CTD): a resource for comparative toxicological studies. J Exp Zool Part A Ecol Genet Physiol 305:689–692
McCubrey JA, Steelman LS, Bertrand FE, Davis NM, Sokolosky M, Abrams SL et al (2014) GSK-3 as potential target for therapeutic intervention in cancer. Oncotarget 5:2881
Mi H, Muruganujan A, Thomas PD (2013) PANTHER in 2013: modeling the evolution of gene function, and other gene attributes, in the context of phylogenetic trees. Nucleic Acids Res 41:D377–D386
Miyagawa K, Sakakura C, Nakashima S, Yoshikawa T, Kin S, Nakase Y et al (2006) Down-regulation of RUNX1, RUNX3 and CBF\(\upbeta \) in hepatocellular carcinomas in an early stage of hepatocarcinogenesis. Anticancer Res 26:3633–3643
Morris JH, Apeltsin L, Newman AM, Baumbach J, Wittkop T, Su G et al (2011) clusterMaker: a multi-algorithm clustering plugin for Cytoscape. BMC Bioinform 12:1
Nanji AA (1998) Apoptosis and alcoholic liver disease. In: Seminars in liver disease. pp 187–190
Nanji AA, Jokelainen K, Rahemtulla A, Miao L, Fogt F, Matsumoto H et al (1999) Activation of nuclear factor kappa B and cytokine imbalance in experimental alcoholic liver disease in the rat. Hepatology 30:934–943
Nelson TH, Jung J-Y, DeLuca TF, Hinebaugh BK, Gabriel St KC, Wall DP (2012) Autworks: a cross-disease network biology application for Autism and related disorders. BMC Med Genomics 5:56
O’shea RS, Dasarathy S, McCullough AJ (2010) Alcoholic liver disease. Hepatology 51:307–328
Peri S, Navarro JD, Amanchy R, Kristiansen TZ, Jonnalagadda CK, Surendranath V et al (2003) Development of human protein reference database as an initial platform for approaching systems biology in humans. Genome Res 13:2363–2371
Pico AR, Kelder T, Van Iersel MP, Hanspers K, Conklin BR, Evelo C (2008) WikiPathways: pathway editing for the people. PLoS Biol 6:e184
Rao R (2009) Endotoxemia and gut barrier dysfunction in alcoholic liver disease. Hepatology 50:638–644
Resat H, Petzold L, Pettigrew MF (2009) Kinetic modeling of biological systems. Comput Syst Biol. pp 311-335
Ribeiro PS, Cortez-Pinto H, Solá S, Castro RE, Ramalho RM, Baptista A et al (2004) Hepatocyte apoptosis, expression of death receptors, and activation of NF-\(\upkappa \)B in the liver of nonalcoholic and alcoholic steatohepatitis patients. Am J Gastroenterol 99:1708–1717
Ron D, Messing RO (2011) Signaling pathways mediating alcohol effects. In: Behavioral neurobiology of alcohol addiction. Springer, pp. 87–126
Saito R, Smoot ME, Ono K, Ruscheinski J, Wang P-L, Lotia S et al (2012) A travel guide to Cytoscape plugins. Nat Methods 9:1069–1076
Sato S, Sugiyama M, Yamamoto M, Watanabe Y, Kawai T, Takeda K et al (2003) Toll/IL-1 receptor domain-containing adaptor inducing IFN-\(\upbeta \) (TRIF) associates with TNF receptor-associated factor 6 and TANK-binding kinase 1, and activates two distinct transcription factors, NF-\(\upkappa \)B and IFN-regulatory factor-3, in the Toll-like receptor signaling. J Immunol 171:4304–4310
Selvarajoo K (2013) Decoding the signaling mechanism of toll-like receptor 4 pathways in wild type and knockouts. In: E-Cell System. Springer, pp 157–167
Selvarajoo K (2006) Discovering differential activation machinery of the Toll-like receptor 4 signaling pathways in MyD88 knockouts. FEBS Lett 580:1457–1464
Sharp GC, Ma H, Saunders PT, Norman JE (2013) A computational model of lipopolysaccharide-induced nuclear factor kappa B activation: a key signalling pathway in infection-induced preterm labour. PloS One 8:e70180
Shengdi LQQXF (2010) Simulating bioreaction processes based on SimBiology. Comput Appl Softw 8:065
Shi L, Kishore R, McMullen MR, Nagy LE (2002) Chronic ethanol increases lipopolysaccharide-stimulated Egr-1 expression in RAW 264.7 macrophages contribution to enhanced tumor necrosis factor \(\upalpha \) production. J Biol Chem 277:14777–14785
Smyth GK (2005) Limma: linear models for microarray data. In: Bioinformatics and computational biology solutions using r and bioconductor. Springer, pp. 397–420
Sun B, Karin M (2008) NF-\(\upkappa \)B signaling, liver disease and hepatoprotective agents. Oncogene 27:6228–6244
Szabo G, Bala S (2010) Alcoholic liver disease and the gut-liver axis. World J Gastroenterol WJG 16(11):1321
Szklarczyk D, Franceschini A, Kuhn M, Simonovic M, Roth A, Minguez P et al (2011) The STRING database in 2011: functional interaction networks of proteins, globally integrated and scored. Nucleic Acids Res 39:D561–D568
Taub R (2004) Liver regeneration: from myth to mechanism. Nat Rev Mol Cell Biol 5:836–847
Uesugi T, Froh M, Arteel GE, Bradford BU, Thurman RG (2001) Toll-like receptor 4 is involved in the mechanism of early alcohol-induced liver injury in mice. Hepatology 34:101–108
Verstak B, Nagpal K, Bottomley SP, Golenbock DT, Hertzog PJ, Mansell A (2009) MyD88 adapter-like (Mal)/TIRAP interaction with TRAF6 is critical for TLR2-and TLR4-mediated NF-\(\upkappa \)B proinflammatory responses. J Biol Chem 284:24192–24203
Walesky C, Apte U (2015) Role of hepatocyte nuclear factor 4\(\upalpha \) (HNF4\(\upalpha )\) in cell proliferation and cancer. Gene Expr 16:101–108
Yao J, Mackman N, Edgington TS, Fan S-T (1997) Lipopolysaccharide induction of the tumor necrosis factor-\(\upalpha \) promoter in human monocytic cells regulation by Egr-1, c-Jun, AND NF-\(\upkappa \)B transcription factors. J Biol Chem 272:17795–17801
Yin M, Bradford BU, Wheeler MD, Uesugi T, Froh M, Goyert SM et al (2001) Reduced early alcohol-induced liver injury in CD14-deficient mice. J Immunol 166:4737–4742
Zhang M, Ouyang Q, Stephenson A, Kane MD, Salt DE, Prabhakar S et al (2008) Interactive analysis of systems biology molecular expression data. BMC Syst Biol 2:23
Zima T, Kalousova M (2005) Oxidative stress and signal transduction pathways in alcoholic liver disease. Alcohol Clin Expe Res 29
Author information
Authors and Affiliations
Corresponding author
Electronic supplementary material
Below is the link to the electronic supplementary material.
Rights and permissions
About this article
Cite this article
Shafaghati, L., Razaghi-Moghadam, Z. & Mohammadnejad, J. A Systems Biology Approach to Understanding Alcoholic Liver Disease Molecular Mechanism: The Development of Static and Dynamic Models. Bull Math Biol 79, 2450–2473 (2017). https://doi.org/10.1007/s11538-017-0336-8
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11538-017-0336-8