Cholestasis, retention of bile acids in the liver, is a leading cause for liver transplantation. Excess amounts of bile acids are cytotoxic and are therefore tightly regulated by nuclear receptors Farnesoid X Receptor (FXR) and Small Heterodimer Partner (SHP). Bile acids are synthesized in the liver and secreted into the intestine for digesting dietary fat. This proposal aims to determine coordinate role of FXR and SHP in controlling bile acid levels in liver and in intestine using genetic mouse models. Successful completion of this project would result in identification of FXR and SHP driven transcriptional gene networks in these above-mentioned tissues. These pilot results will enable us to perform detailed analysis and provide mechanistic insights into the underpinnings of cholestasis.

Public Health Relevance

Accumulation of bile acids in liver is the inherent cause that leads to cholestatic disorders. Bile acids auto-regulate their concentration via negative feed back pathway elicited by Farnesoid X Receptor (FXR) and Small Heterodimer Partner (SHP). This proposal will identify novel FXR and SHP target genes that may be used for diagnosis and pharmacological intervention in cholestasis.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Small Research Grants (R03)
Project #
1R03HD080011-01A1
Application #
8970254
Study Section
Pediatrics Subcommittee (CHHD)
Program Officer
Giacoia, George
Project Start
2015-07-10
Project End
2017-06-30
Budget Start
2015-07-10
Budget End
2016-06-30
Support Year
1
Fiscal Year
2015
Total Cost
$74,858
Indirect Cost
$24,858
Name
University of Illinois Urbana-Champaign
Department
Physiology
Type
Schools of Arts and Sciences
DUNS #
041544081
City
Champaign
State
IL
Country
United States
Zip Code
61820
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Desai, Moreshwar S; Mathur, Bhoomika; Eblimit, Zeena et al. (2017) Bile acid excess induces cardiomyopathy and metabolic dysfunctions in the heart. Hepatology 65:189-201
Akinrotimi, Oludemilade; Riessen, Ryan; VanDuyne, Philip et al. (2017) Small heterodimer partner deletion prevents hepatic steatosis and when combined with farnesoid X receptor loss protects against type 2 diabetes in mice. Hepatology 66:1854-1865