The identification of nuclear receptors associated with hepatic steatosis to develop and extend adverse outcome pathways

Abstract

The development of adverse outcome pathways (AOPs) is becoming a key component of twenty-first century toxicology. AOPs provide a conceptual framework that links the molecular initiating event to an adverse outcome through organized toxicological knowledge, bridging the gap from chemistry to toxicological effect. As nuclear receptors (NRs) play essential roles for many physiological processes within the body, they are used regularly as drug targets for therapies to treat many diseases including diabetes, cancer and neurodegenerative diseases. Due to the heightened development of NR ligands, there is increased need for the identification of related AOPs to facilitate their risk assessment. Many NR ligands have been linked specifically to steatosis. This article reviews and summarizes the role of NR and their importance with links between NR examined to identify plausible putative AOPs. The following NRs are shown to induce hepatic steatosis upon ligand binding: aryl hydrocarbon receptor, constitutive androstane receptor, oestrogen receptor, glucocorticoid receptor, farnesoid X receptor, liver X receptor, peroxisome proliferator-activated receptor, pregnane X receptor and the retinoic acid receptor. A preliminary, putative AOP was formed for NR binding linked to hepatic steatosis as the adverse outcome.

Keywords:

• Adverse outcome pathway (AOP)
• hepatic toxicity
• mechanisms of toxicity
• nuclear receptor
• steatosis

Acknowledgements

The comments of the three reviewers selected by the editor and anonymous to the authors were helpful in revising the article.

Declaration of interest

The research leading to these results has received funding from the European Community’s Seventh Framework Program (FP7/2007-2013) under grant agreement no. 266835 and from Cosmetics Europe. More information is available at www.cosmostox.eu.