Modes-of-Action Related to Repeated Dose Toxicity: Tissue-Specific Biological Roles of PPAR ? Ligand-Dependent Dysregulation in Nonalcoholic Fatty Liver Disease.
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ABSTRACT: 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 ? 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 ? . Over 300 papers were ranked according to preliminary defined criteria and used as reliable and significant sources of data about the PPAR ? -dependent prosteatotic MoA. A detailed analysis was performed regarding proteins which PPAR ? -mediated expression changes had been confirmed to be prosteatotic by most experimental evidence. Two probable toxicological MoAs from PPAR ? ligand binding to NAFLD were described according to the Organisation for Economic Cooperation and Development (OECD) concepts: (i) PPAR ? activation in hepatocytes and (ii) PPAR ? 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.
SUBMITTER: Al Sharif M
PROVIDER: S-EPMC3977565 | biostudies-literature | 2014
REPOSITORIES: biostudies-literature
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