Yan, Jiong
(2018)
HEPATIC XENOBIOTIC RECEPTORS IN THE UBIQUITIN-PROTEASOME SYSTEM.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
Constitutive androstane receptor (CAR) and aryl hydrocarbon receptor (AhR) are liver-enriched xenobiotic receptors that are essential in the regulation of drug-metabolizing enzymes (DMEs) and drug transporters. Emerging evidence has also implicated CAR and AhR in the energy metabolism, cell proliferation and immune response, in addition to their classical function of xenobiotic detoxification. The cellular effects mediated by these xenobiotic receptors can be achieved canonically by the transcriptional modulation via direct interaction with the genomic DNA. There are also indirect mechanisms via protein-protein interactions by which CAR and AhR can alter the transcriptome. The preliminary results together with previous studies by others have suggested an interplay between the xenobiotic receptors and ubiquitin-proteasome system (UPS). In this dissertation study, I studied the E3 ubiquitin ligase activity of CAR and AhR in the context of hepatic gluconeogenesis and hepatic stellate cell (HSC) activation, respectively. My results demonstrated that (1) CAR suppresses hepatic gluconeogenic gene expression through post-translational regulation of the subcellular localization and degradation of PPAR-γ coactivator 1α (PGC1α). Activated CAR translocates into the nucleus and serves as a substrate adaptor protein recruiting PGC1α to the Cullin1 E3 ligase complex for ubiquitylation. The interaction between CAR and PGC1α also leads to their sequestration within the promyelocytic leukemia protein-nuclear bodies (PML-NBs), where PGC1α and CAR subsequently undergo proteasomal degradation, which is required for CAR-mediated inhibition of PGC1α. (2) AhR negatively regulates HSC activation by disrupting the interaction of Smad3 with β-catenin and impairing β-catenin-dependent stabilization of phosphorylated Smad2/3, which is independent of its E3 ubiquitin ligase activity. AhR is highly expressed in HSCs and activation of AhR prevents fibrogenesis and proliferation of HSCs. The expression of AhR in HSCs declines with the onset of HSC activation. Primary HSCs isolated from the AhR-/- mice exhibits accelerated spontaneous activation. Treatment with an AhR antagonist promotes, whereas the AhR agonists inhibit the activation of mouse and human HSCs, respectively. In vivo ablation of AhR in HSCs sensitizes mice to liver fibrosis. Overall, this dissertation elucidates a novel concept of xenobiotic receptors as the essential components in the UPS.
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Details
| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
|
| ETD Committee: |
| Title | Member | Email Address | Pitt Username | ORCID |
|---|
| Committee Chair | Xie, Wen | | | | | Committee Member | DeFranco, Donald | | | | | Committee Member | Johnston, Paul | | | | | Committee Member | Ma, Xiaochao | | | | | Committee Member | Wan, Yong | | | |
|
| Date: |
15 March 2018 |
| Date Type: |
Publication |
| Defense Date: |
27 February 2018 |
| Approval Date: |
15 March 2018 |
| Submission Date: |
15 March 2018 |
| Access Restriction: |
1 year -- Restrict access to University of Pittsburgh for a period of 1 year. |
| Number of Pages: |
139 |
| 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: |
Xenobiotic receptor, CAR, AhR, gluconeogenesis, liver fibrosis |
| Date Deposited: |
15 Mar 2018 16:08 |
| Last Modified: |
15 Mar 2019 05:15 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/33889 |
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