Modes-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.
Institute of Biophysics and Biomedical Engineering, Bulgarian Academy of Sciences, Acad. G. Bonchev Street, Building 105, 1113 Sofia, Bulgaria.
Merilin
0000-0003-2182-2006
M
Al Sharif
Institute of Biophysics and Biomedical Engineering, Bulgarian Academy of Sciences, Acad. G. Bonchev Street, Building 105, 1113 Sofia, Bulgaria.
Petko
0000-0003-1320-2173
P
Alov
Institute of Biophysics and Biomedical Engineering, Bulgarian Academy of Sciences, Acad. G. Bonchev Street, Building 105, 1113 Sofia, Bulgaria.
Vessela
V
Vitcheva
Institute of Biophysics and Biomedical Engineering, Bulgarian Academy of Sciences, Acad. G. Bonchev Street, Building 105, 1113 Sofia, Bulgaria.
Ilza
0000-0001-5412-1586
I
Pajeva
Institute of Biophysics and Biomedical Engineering, Bulgarian Academy of Sciences, Acad. G. Bonchev Street, Building 105, 1113 Sofia, Bulgaria.
Ivanka
I
Tsakovska