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Uppal, Hirdesh (2007) REGULATORY NETWORKS OF PXR, CAR AND LXR IN CHOLESTEROL AND BILE ACID METABOLISM. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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The orphan nuclear receptors Pregnane X Receptor (PXR) and Constitutive Androstane Receptor (CAR) have been proposed to play an important role in the detoxification of xeno- and endobiotics by regulating the expression of detoxifying enzymes and transporters. We showed that the combined loss of PXR and CAR resulted in a significantly heightened sensitivity to bile acid toxicity in a sex-specific manner. The increased sensitivity in males was associated with genotype-specific suppression of bile acid transporters and loss of bile acid-mediated down regulation of small heterodimer partner, whereas the transporter suppression was modest or absent in the female DKO mice. The liver X receptors (LXRs), including the alpha and beta isoforms were identified as sterol sensors that regulate cholesterol and lipid homeostasis and macrophage functions. We found that activation of LXRĄ in transgenic mice or with LXR ligands confers a female-specific resistance to lithocholic acid (LCA)-induced hepatotoxicity and bile duct ligation (BDL)-induced cholestasis. In contrast, LXR alpha and beta double knockout mice (LXR DKO) exhibited heightened cholestatic sensitivity. The LCA and BDL resistance in transgenic mice was associated with an increased expression of bile acid detoxifying sulfotransferase 2A (SULT2A) and selected members of the bile acid transporters. We also showed that genetic or pharmacological activation of the orphan nuclear receptor liver X receptor (LXR) sensitized mice to cholesterol gallstone disease (CGD) induced by a high cholesterol lithogenic diet. LXR-promoted CGD was associated with increased expression of several canalicular transporters that efflux cholesterol and phospholipids, leading to higher biliary concentrations of cholesterol and phospholipids. The biliary bile salt concentration was reduced in these mice, resulting in increased cholesterol saturation index (CSI). Interestingly, the lithogenic effect of LXR was completely abolished in the low-density lipoprotein receptor (LDLR) null background or when the mice were treated with Ezetimibe, a cholesterol-lowering drug that blocks the intestinal dietary cholesterol absorption. We propose that LXRs have evolved to have dual function in maintaining cholesterol and bile acid homeostasis.


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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairDeFranco, Donald Bdod1@pitt.eduDOD1
Committee MemberZhao, Allan Zazhao@pitt.eduAZHAO
Committee MemberVenkataramanan, Ramanrv@pitt.eduRV
Committee MemberSingh, Shivendra Vsvs2@pitt.eduSVS2
Committee MemberXie, Wenwex6@pitt.eduWEX6
Date: 5 April 2007
Date Type: Completion
Defense Date: 7 August 2006
Approval Date: 5 April 2007
Submission Date: 2 April 2007
Access Restriction: 5 year -- Restrict access to University of Pittsburgh for a period of 5 years.
Institution: University of Pittsburgh
Schools and Programs: School of Medicine > Molecular Pharmacology
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: bile acid metabolism; cholesterol metabolism; gene regulation; nuclear receptors; orphan nuclear receptor; transgenic mice; xenobiotics; gallstone disease; LXR; PXR; CAR
Other ID:, etd-04022007-144214
Date Deposited: 10 Nov 2011 19:33
Last Modified: 15 Nov 2016 13:38


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