Figure 1: Effective therapeutic approach through GEM modelling.

Schematic illustration of how a consensus GEM for hepatocytes, iHepatocytes2322, may contribute to the development of effective therapeutic approaches for NAFLD patients. The HMR 2.0 database was constructed through the use of previously published GEMs and pathway databases, including KEGG, HumanCyc, Reactome and LIPIDMAPS Lipidomics Gateway. Elements of lipid metabolism were included in the HMR database to understand the effect of the lipids and their interactions during the appearance of NAFLD. The HMR 2.0 database was used for reconstruction of iHepatocytes2322 based on proteomics data in the HPA, transcriptomics data in NAFLD patients and previously published hepatocytes models. During the reconstruction process, iHepatocytes2322 was employed for the improvement of proteomics data through identification and re-annotation of putative false-negative proteins. The resulting GEM was used for the analysis of clinical data obtained from NAFLD patients to investigate the alterations in their hepatocyte metabolism and eventually for the discovery of biomarkers and identifying therapeutic targets. Through our systems biology-based analysis, potential biomarkers for diagnosing NASH and for subcatogorizing NAFLD patients were discovered. Furthermore, a list of candidate therapeutic targets was identified to develop efficient treatments for NASH patients.