One of the central features of the hepatic response to inflammation is the suppression of a broad array of core physiological functions, including those essential to maintaining hepatobiliary transport of bile acids. In addition to post-translational regulation of transporter protein membrane expression and function, inflammation-based cell signaling pathways act on nuclear targets to transcriptionally suppress the expression of the essential bile acid transporters Ntcp and Bsep. The central Type II NR superfamily member and heterodimer partner RXRa is a major transcriptional activator of these two genes, and its nuclear activity is rapidly suppressed by inflammation-based cell signaling. Reduced RXRa target gene expression leads to multiple functional impairments and damage to hepatocytes. How cell signaling pathways suppress RXRa function is unknown, and forms the basis for the explorations and interventions proposed in this application. The overall unifying hypothesis is that inflammatory cell signaling pathways reduce nuclear activity of RXRa via a coordinated cascade of post-translational modification, nuclear export and proteasomal degradation. The following four Aims will determine the underlying physiology, and pathophysiology of inflammation-mediated cholestasis and explore novel therapeutics.
Aim 1 : Define the molecular mechanisms mediating IL-1(3-induced nuclear export of RXRa.
Aim 2 : Determine roles for ubiquitination and proteasomal degradation of RXRa in response to IL-1 IB- induced signaling pathways.
Aim 3 : Explore crosstalk between bile acid and IL-1p-mediated pathways that modify RXRa function.
Aim 4 : Investigate the effects of anti-inflammatory agents on transporter gene and protein expression in the IPS model of hepatic inflammation. It is through a combined in vitro and in vivo approach that we can explore the mechanisms, mediators, and potential therapeutic interventions aimed at restoring RXRa function, hepatobiliary transporter function, and bile flow, in the setting of inflammation-mediated cell signaling in liver. The ultimate goal of these studies is to provide rational molecular targets for the testing of therapies specifically designed to interfere with the damaging consequences of inflammation-mediated pathways, which are engaged in nearly all forms of acute and chronic liver diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK056239-10
Application #
7800419
Study Section
Hepatobiliary Pathophysiology Study Section (HBPP)
Program Officer
Serrano, Jose
Project Start
1999-09-01
Project End
2011-10-20
Budget Start
2010-04-01
Budget End
2011-10-20
Support Year
10
Fiscal Year
2010
Total Cost
$279,200
Indirect Cost
Name
Baylor College of Medicine
Department
Pediatrics
Type
Schools of Medicine
DUNS #
051113330
City
Houston
State
TX
Country
United States
Zip Code
77030
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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
Dawson, Paul A; Karpen, Saul J (2015) Intestinal transport and metabolism of bile acids. J Lipid Res 56:1085-99
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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
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Kosters, Astrid; Sun, Deqiang; Wu, Hao et al. (2013) Sexually dimorphic genome-wide binding of retinoid X receptor alpha (RXR?) determines male-female differences in the expression of hepatic lipid processing genes in mice. PLoS One 8:e71538

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