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.
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.
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