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

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 toxicol...

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Bibliographic Details
Published in:Critical reviews in toxicology 2016-02, Vol.46 (2), p.138-152
Main Authors: Mellor, Claire L., Steinmetz, Fabian P., Cronin, Mark T. D.
Format: Article
Language:English
Subjects:
Adverse outcome pathway (AOP)
Animals
Chemical and Drug Induced Liver Injury - etiology
Chemical and Drug Induced Liver Injury - pathology
Disease Models, Animal
Drug Delivery Systems
Fatty Liver - chemically induced
Fatty Liver - pathology
hepatic toxicity
Humans
Liver - drug effects
Liver - metabolism
mechanisms of toxicity
Models, Biological
nuclear receptor
Receptors, Cytoplasmic and Nuclear - metabolism
Risk Assessment
steatosis
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Summary: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.
ISSN:1040-8444
1547-6898
DOI:10.3109/10408444.2015.1089471