Liver X receptor agonist T0901317 induced liver perturbation in zebrafish: Histological, gene set enrichment and expression analyses

BackgroundLiver X receptor (LXR), a ligand-activated transcription factor, regulates important biological processes. It has been associated with pathology and proposed as a therapeutic target. The zebrafish is a new vertebrate model for disease modeling, drug and toxicity screening and will be interesting to test for its potential for LXR-related studies.MethodsAdult male fish were exposed to LXR agonist T0901317 at 20, 200 and 2000 nM for 96 h and the livers were sampled for histological, microarray and qRT-PCR analyses.ResultsHistological analysis suggests dose-dependent perturbation of carbohydrate and lipid metabolisms by T0901317 in the liver, which lead to hepatocyte swelling and cell death. Microarray data revealed several conserved effects of T0901317 with mammalian models, including up-regulation of LXR-targeted genes, modulation of biological pathways associated with proteasome, cell death, extracellular matrix and adhesions, maturity onset diabetes of the young and lipid beta oxidation. Interestingly, this study identified the complement and coagulation systems as down-regulated by T0901317 for the first time, potentially via transcriptional repression by LXR activation. qRT-PCR validated the expression of 16 representative genes, confirming activation of LXR signaling and down-regulation of these biological pathways by T0901317 which could be linked to the anti-thrombogenic, anti-atherogenic and anti-inflammatory actions, as well as metabolic disruptions via LXR activation.Conclusion and general significanceOur study underscores the potential of using zebrafish model coupled with transcriptomic analysis to capture pharmacological and toxicological or pathological events induced by LXR modulators.

► Zebrafish treated with LXR agonist T0901317 were analyzed by microarray and histology.
► T0901317 perturbed carbohydrate and lipid metabolism with swelling hepatocytes.
► Effects of T0901317 on LXR modulated pathways were conserved in zebrafish and mammals.
► Microarray analysis identified complement and coagulation systems as novel LXR targets.
► PCR validation confirmed T0901317 induced LXR signaling and pharmacological effects.