title: Liver X receptor agonist T0901317 induced liver perturbation in zebrafish: histological, gene set enrichment and expression analyses.
abstract: BACKGROUND
  Liver 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.
  
  
  METHODS
  Adult male fish were exposed to LXR agonist T0901317 at 20, 200 and 2000nM for 96h and the livers were sampled for histological, microarray and qRT-PCR analyses.
  
  
  RESULTS
  Histological 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.
  
  
  CONCLUSIONS
  Our study underscores the potential of using zebrafish model coupled with transcriptomic analysis to capture pharmacological and toxicological or pathological events induced by LXR modulators.
authors: Department of Biological Sciences, National University of Singapore, Singapore.
authors: Hendrian
authors: H
authors: Sukardi
authors: Xiaoyan
authors: X
authors: Zhang
authors: Eei Yin
authors: EY
authors: Lui
authors: Choong Yong
authors: CY
authors: Ung
authors: Sinnakaruppan
authors: S
authors: Mathavan
authors: Zhiyuan
authors: Z
authors: Gong
authors: Siew Hong
authors: SH
authors: Lam
mesh_terms: D000818:Animals; D050260:Carbohydrate Metabolism / Q000187:drug effects; D002448:Cell Adhesion / Q000187:drug effects; D015536:Down-Regulation / Q000187:drug effects; D005109:Extracellular Matrix / Q000187:drug effects; D006845:Hydrocarbons, Fluorinated / Q000494:pharmacology* / Q000633:toxicity; D050356:Lipid Metabolism / Q000187:drug effects; D008099:Liver / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D000071518:Liver X Receptors; D008297:Male; D057093:Orphan Nuclear Receptors / Q000819:agonists* / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D013449:Sulfonamides / Q000494:pharmacology* / Q000633:toxicity; D018675:Toxicity Tests; D015027:Zebrafish; D005466:Fluorocarbons; D000096926:Benzenesulfonamides
chemical_list: D006845:Hydrocarbons, Fluorinated; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D013449:Sulfonamides; C423915:T0901317; D005466:Fluorocarbons; D000096926:Benzenesulfonamides