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 21st century toxicology. AOPs provide a conceptual framework that links the molecular initiating event to an adverse outcome through organised 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 paper reviews and summarises 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.