biostudies-literatureUnknown2014Al Sharif MComprehensive understanding of the precise mode of action/adverse outcome pathway (MoA/AOP) of chemicals becomes a key step towards superseding the current repeated dose toxicity testing methodology with new generation predictive toxicology tools. The description and characterization of the toxicological MoA leading to non-alcoholic fatty liver disease (NAFLD) are of specific interest, due to its increasing incidence in the modern society. Growing evidence stresses on the PPAR γ ligand-dependent dysregulation as a key molecular initiating event (MIE) for this adverse effect. The aim of this work was to analyze and systematize the numerous scientific data about the steatogenic role of PPAR γ . Over 300 papers were ranked according to preliminary defined criteria and used as reliable and significant sources of data about the PPAR γ -dependent prosteatotic MoA. A detailed analysis was performed regarding proteins which PPAR γ -mediated expression changes had been confirmed to be prosteatotic by most experimental evidence. Two probable toxicological MoAs from PPAR γ ligand binding to NAFLD were described according to the Organisation for Economic Cooperation and Development (OECD) concepts: (i) PPAR γ activation in hepatocytes and (ii) PPAR γ inhibition in adipocytes. The possible events at different levels of biological organization starting from the MIE to the organ response and the connections between them were described in details.PPAR research432647https://www.ebi.ac.uk/biostudies/studies/S-EPMC3977565biostudies-literatureModes-of-Action Related to Repeated Dose Toxicity: Tissue-Specific Biological Roles of PPAR γ Ligand-Dependent Dysregulation in Nonalcoholic Fatty Liver Disease.PMC3977565Pajeva IAlov PAl Sharif MTsakovska IVitcheva VfalseModes-of-Action Related to Repeated Dose Toxicity: Tissue-Specific Biological Roles of PPAR γ Ligand-Dependent Dysregulation in Nonalcoholic Fatty Liver Disease.Comprehensive understanding of the precise mode of action/adverse outcome pathway (MoA/AOP) of chemicals becomes a key step towards superseding the current repeated dose toxicity testing methodology with new generation predictive toxicology tools. The description and characterization of the toxicological MoA leading to non-alcoholic fatty liver disease (NAFLD) are of specific interest, due to its increasing incidence in the modern society. Growing evidence stresses on the PPAR γ ligand-dependent dysregulation as a key molecular initiating event (MIE) for this adverse effect. The aim of this work was to analyze and systematize the numerous scientific data about the steatogenic role of PPAR γ . Over 300 papers were ranked according to preliminary defined criteria and used as reliable and significant sources of data about the PPAR γ -dependent prosteatotic MoA. A detailed analysis was performed regarding proteins which PPAR γ -mediated expression changes had been confirmed to be prosteatotic by most experimental evidence. Two probable toxicological MoAs from PPAR γ ligand binding to NAFLD were described according to the Organisation for Economic Cooperation and Development (OECD) concepts: (i) PPAR γ activation in hepatocytes and (ii) PPAR γ inhibition in adipocytes. The possible events at different levels of biological organization starting from the MIE to the organ response and the connections between them were described in details.2014-01-01T00:00:00Z20142024-11-21T09:55:00.447Z2019-03-27T01:24:31ZS-EPMC39775652477216410.1155/2014/432647