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.

Public Health Relevance

The liver responds to inflammation by changing the expression of thousands of genes, due to changes in the function of a host of nuclear proteins. These nuclear proteins drive liver gene expression for many core functions including the handling of sugars, fats, and bile formation. How they are altered in response to inflammation is poorly understood. These studies are aimed at uncovering the mechanisms and targets of inflammation in liver, with the expectation to provide a detailing mapping and opportunities for therapeutic intervention.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
5R01DK056239-13
Application #
8677876
Study Section
Hepatobiliary Pathophysiology Study Section (HBPP)
Program Officer
Serrano, Jose
Project Start
Project End
Budget Start
Budget End
Support Year
13
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Emory University
Department
Pediatrics
Type
Schools of Medicine
DUNS #
City
Atlanta
State
GA
Country
United States
Zip Code
30322
Karpen, Saul J; Dawson, Paul A (2015) Not all (bile acids) who wander are lost: the first report of a patient with an isolated NTCP defect. Hepatology 61:24-7
Dawson, Paul A; Karpen, Saul J (2014) Bile acids reach out to the spinal cord: new insights to the pathogenesis of itch and analgesia in cholestatic liver disease. Hepatology 59:1638-41
Kosters, Astrid; Felix, Julio C; Desai, Moreshwar S et al. (2014) Impaired bile acid handling and aggravated liver injury in mice expressing a hepatocyte-specific RXR* variant lacking the DNA-binding domain. J Hepatol 60:362-9
Schneider Aguirre, Rebecca; Karpen, Saul J (2013) Inflammatory mediators increase SUMOylation of retinoid X receptor * in a c-Jun N-terminal kinase-dependent manner in human hepatocellular carcinoma cells. Mol Pharmacol 84:218-26
Kosters, Astrid; Tian, Feng; Wan, Yu-Jui Yvonne et al. (2012) Gene-specific alterations of hepatic gene expression by ligand activation or hepatocyte-selective inhibition of retinoid X receptor-ýý signalling during inflammation. Liver Int 32:321-30
Desai, Moreshwar S; Zainuer, Shabier; Kennedy, Curtis et al. (2011) Cardiac structural and functional alterations in infants and children with biliary atresia, listed for liver transplantation. Gastroenterology 141:1264-72, 1272.e1-4
Baghdasaryan, Anna; Claudel, Thierry; Kosters, Astrid et al. (2010) Curcumin improves sclerosing cholangitis in Mdr2-/- mice by inhibition of cholangiocyte inflammatory response and portal myofibroblast proliferation. Gut 59:521-30
Karpen, Saul J; Trauner, Michael (2010) The new therapeutic frontier--nuclear receptors and the liver. J Hepatol 52:455-62
Arrese, M; Karpen, S J (2010) Nuclear receptors, inflammation, and liver disease: insights for cholestatic and fatty liver diseases. Clin Pharmacol Ther 87:473-8
Kosters, Astrid; Karpen, Saul J (2010) The role of inflammation in cholestasis: clinical and basic aspects. Semin Liver Dis 30:186-94

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