title: The role of retinoic acid in hepatic lipid homeostasis defined by genomic binding and transcriptome profiling.
abstract: BACKGROUND
  The eyes and skin are obvious retinoid target organs. Vitamin A deficiency causes night blindness and retinoids are widely used to treat acne and psoriasis. However, more than 90% of total body retinol is stored in liver stellate cells. In addition, hepatocytes produce the largest amount of retinol binding protein and cellular retinoic acid binding protein to mobilize retinol from the hepatic storage pool and deliver retinol to its receptors, respectively. Furthermore, hepatocytes express the highest amount of retinoid x receptor alpha (RXRα) among all the cell types. Surprisingly, the function of endogenous retinoids in the liver has received very little attention.
  
  
  RESULTS
  Based on the data generated from chromatin immunoprecipitation followed by sequencing, the global DNA binding of transcription factors including retinoid x receptor α (RXRα) along with its partners i.e. retinoic acid receptor α (RARα), pregnane x receptor (PXR), liver x receptor (LXR), farnesoid x receptor (FXR), and peroxisome proliferator-activated receptor α (PPARα) has been established. Based on the binding, functional annotation illustrated the role of those receptors in regulating hepatic lipid homeostasis. To correlate the DNA binding data with gene expression data, the expression patterns of 576 genes that regulate lipid homeostasis were studied in wild type and liver RXRα-null mice treated with and without RA. The data showed that RA treatment and RXRα-deficiency had opposite effects in regulating lipid homeostasis. A subset of genes (114), which could clearly differentiate the effect of ligand treatment and receptor deficiency, were selected for further functional analysis. The expression data suggested that RA treatment could produce unsaturated fatty acids and induce triglyceride breakdown, bile acid secretion, lipolysis, and retinoids elimination. In contrast, RXRα deficiency might induce the synthesis of saturated fatty acids, triglyceride, cholesterol, bile acids, and retinoids. In addition, DNA binding data indicated extensive cross-talk among RARα, PXR, LXR, FXR, and PPARα in regulating those RA/RXRα-dependent gene expression levels. Moreover, RA reduced serum cholesterol, triglyceride, and bile acid levels in mice.
  
  
  CONCLUSIONS
  We have characterized the role of hepatic RA for the first time. Hepatic RA mediated through RXRα and its partners regulates lipid homeostasis.
authors: Department of Medical Pathology and Laboratory Medicine, University of California, Davis Health Systems, Sacramento 95817, CA, USA. yjywan@ucdavis.edu.
authors: Yuqi
authors: Y
authors: He
authors: Lei
authors: L
authors: Gong
authors: Yaping
authors: Y
authors: Fang
authors: Qi
authors: Q
authors: Zhan
authors: Hui-Xin
authors: HX
authors: Liu
authors: Yanliu
authors: Y
authors: Lu
authors: Grace L
authors: GL
authors: Guo
authors: Lois
authors: L
authors: Lehman-McKeeman
authors: Jianwen
authors: J
authors: Fang
authors: Yu-Jui Yvonne
authors: YJ
authors: Wan
mesh_terms: D000818:Animals; D001647:Bile Acids and Salts / Q000097:blood; D001665:Binding Sites; D002784:Cholesterol / Q000097:blood; D005786:Gene Expression Regulation; D016678:Genome; D006706:Homeostasis / Q000235:genetics; D050356:Lipid Metabolism / Q000187:drug effects / Q000235:genetics*; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011485:Protein Binding; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism; D059467:Transcriptome; D014212:Tretinoin / Q000494:pharmacology / Q000502:physiology*; D014280:Triglycerides / Q000097:blood
chemical_list: D001647:Bile Acids and Salts; D018160:Receptors, Cytoplasmic and Nuclear; D014280:Triglycerides; D014212:Tretinoin; D002784:Cholesterol
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