Lee, Jung Hoon
(2009)
The role of the aryl hydrocarbon receptor and the liver X receptor in gene regulation and metabolic homeostasis.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
The aryl hydrocarbon receptor (AhR) is a PAS domain transcriptional factor also known as the ¡§dioxin receptor¡¨ or ¡§xenobiotic receptor.¡¨ My thesis work has uncovered an endobiotic role for AhR in hepatic steatosis and other metabolic functions. Activation of AhR induced spontaneous hepatic steatosis, which is characterized by the accumulation of triglycerides. The steatotic effect of AhR was likely due to the combined upregulation of fatty acid translocase CD36/FAT, suppression of fatty acid oxidation, inhibition of hepatic export of triglycerides, and an increase in the mobilization of peripheral fat. Promoter analysis established CD36 as a novel transcriptional target of AhR. Moreover, the steatotic effect of an AhR agonist was inhibited in mice deficient of CD36. Results from this study may help to establish AhR and its target fatty acid translocase CD36 as attractive targets for intervention in fatty liver disease. The liver X receptors (LXRs), both the ƒÑ and ƒÒ isoforms, are nuclear receptors identified as sterol sensors that modulate cholesterol and lipid metabolism and homeostasis. In the second part of my thesis research, I report a novel LXR-mediated mechanism of androgen deprivation. Genetic or pharmacological activation of the liver X receptor (LXR) in vivo lowered androgenic activity by inducing the hydroxysteroid sulfotransferase 2A1 (SULT2A1), an enzyme essential for the metabolic deactivation of androgens. Activation of LXR also inhibited the expression of steroid sulfatase (STS) in the prostate, which may have helped to prevent the local conversion of sulfonated androgens back to active metabolites. At the physiological level, activation of LXR in mice inhibited androgen-dependent prostate regeneration in castrated mice. Treatment with LXR agonists inhibited androgen-dependent proliferation of prostate cancer cells in LXR- and SULT2A1-dependent manner. The ability of LXRs to regulate androgen metabolism makes them novel therapeutic targets for the treatment and prevention of hormone-dependent prostate cancer. Taken together, my work has revealed novel functions of AhR in lipid metabolism and LXR in androgen deprivation. It is hoped that understandings of the endobiotic functions of AhR and LXR may establish these two receptors as therapeutic targets for the management of metabolic disease in humans.
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Details
| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
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| ETD Committee: |
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| Date: |
14 April 2009 |
| Date Type: |
Completion |
| Defense Date: |
7 April 2009 |
| Approval Date: |
14 April 2009 |
| Submission Date: |
9 April 2009 |
| Access Restriction: |
No restriction; Release the ETD for access worldwide immediately. |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
School of Pharmacy > Pharmaceutical Sciences |
| Degree: |
PhD - Doctor of Philosophy |
| Thesis Type: |
Doctoral Dissertation |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
androgen deprivation; aryl hydrocarbon receptor; gene regulation; hepatic steatosis; nuclear receptor; transgenic mice |
| Other ID: |
http://etd.library.pitt.edu/ETD/available/etd-04092009-173105/, etd-04092009-173105 |
| Date Deposited: |
10 Nov 2011 19:35 |
| Last Modified: |
15 Nov 2016 13:39 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/6930 |
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