OR23-5 Genomic Binding and Transcriptome Profiling Defines the Role of Retinoic Acid in Hepatic Lipid Homeostasis

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: OR23-Metabolic & Stress Receptors in Energy Homeostasis
Sunday, June 16, 2013: 11:15 AM-12:45 PM
Presentation Start Time: 12:15 PM
Room 256 (Moscone Center)
Yuqi He*1, Lei Gong2, Yaping Fang3, Qi Zhan4, Hui-Xin Liu1, Grace L. Guo5, Lois Lehman-McKeeman2, Jianwen Fang3, Yanliu Lu1 and Yu-Jui Yvonne Wan1
1Sch of Med Univ of California, D, Sacramento, CA, 2Bristol-Myers Squibb Company, 3University of Kansas, Lawrence, KS, 4Guangzhou First Municipal People’s Hospital, Guangzhou, China, 5Ernest Mario School of Pharmacy
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. Thus, the current study aims to identify the bona fide RXRα and RARα targets in the liver. 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 expressions. Moreover, RA reduced serum cholesterol, triglyceride, and bile acid levels in mice. Taken together, we have characterized the role of hepatic RA for the first time. Hepatic RA mediated through RXRα and its partners regulates lipid homeostasis.

Nothing to Disclose: YH, LG, YF, QZ, HXL, GLG, LL, JF, YL, YJYW

*Please take note of The Endocrine Society's News Embargo Policy at http://www.endo-society.org/endo2013/media.cfm

Sources of Research Support: This study is supported by grants funded by National Institutes of Health DK092100 and CA53596