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)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK056239-13
Application #
8677876
Study Section
Hepatobiliary Pathophysiology Study Section (HBPP)
Program Officer
Serrano, Jose
Project Start
1999-09-01
Project End
2018-06-30
Budget Start
2014-07-01
Budget End
2015-06-30
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
Kosters, Astrid; Abebe, Demesew F; Felix, Julio C et al. (2016) Inflammation-associated upregulation of the sulfated steroid transporter Slc10a6 in mouse liver and macrophage cell lines. Hepatol Res 46:794-803
Rao, Anuradha; Kosters, Astrid; Mells, Jamie E et al. (2016) Inhibition of ileal bile acid uptake protects against nonalcoholic fatty liver disease in high-fat diet-fed mice. Sci Transl Med 8:357ra122
Dawson, Paul A; Karpen, Saul J (2015) Intestinal transport and metabolism of bile acids. J Lipid Res 56:1085-99
Desai, Moreshwar S; Eblimit, Zeena; Thevananther, Sundararajah et al. (2015) Cardiomyopathy reverses with recovery of liver injury, cholestasis and cholanemia in mouse model of biliary fibrosis. Liver Int 35:1464-77
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
El Kasmi, Karim C; Anderson, Aimee L; Devereaux, Michael W et al. (2013) Phytosterols promote liver injury and Kupffer cell activation in parenteral nutrition-associated liver disease. Sci Transl Med 5:206ra137
Kosters, Astrid; Sun, Deqiang; Wu, Hao et al. (2013) Sexually dimorphic genome-wide binding of retinoid X receptor alpha (RXRα) determines male-female differences in the expression of hepatic lipid processing genes in mice. PLoS One 8:e71538
Schneider Aguirre, Rebecca; Karpen, Saul J (2013) Inflammatory mediators increase SUMOylation of retinoid X receptor α in a c-Jun N-terminal kinase-dependent manner in human hepatocellular carcinoma cells. Mol Pharmacol 84:218-26

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