Molecular Regulation of Hepatic Transporters

Emory University, Atlanta GA

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Abstract

DESCRIPTION (provided by applicant): Transcriptional suppression of the function of the Type II nuclear receptor (NR) superfamily member and heterodimer partner to ~17 NRs in liver-the Retinoid X Receptor ? (RXR?, NR2B1)-underlies most of the inflammation-mediated changes in liver biology, including a suppression of bile acid (BA) transport. The overall unifying hypothesis is that inflammatory cell signaling pathways modulate RXR? activities by post-translational modification (PTM)->altered genome-wide RXR? chromatin site occupancy->reduced RXR? heterodimer function->broad changes in RXR?-dependent gene expression in liver->increased BA retention->exacerbation of liver damage. These studies are aimed at two PTMs-phosphorylation of S260 and SUMOylation of K108. Moreover, detailed ChIP-SEQ mapping of the alterations in RXR? genome wide binding in response to bile acids and inflammation in mouse liver, along with potential attenuation with select therapeutic NR ligands will provide insight into the whole liver changes in RXR? heterodimer site chromatin occupancy, and the effectiveness of NR ligands.