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Yan, Jiong (2018) HEPATIC XENOBIOTIC RECEPTORS IN THE UBIQUITIN-PROTEASOME SYSTEM. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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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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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Yan, Jiongjiy45@pitt.edujiy450000-0002-3010-8982
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairXie, Wen
Committee MemberDeFranco, Donald
Committee MemberJohnston, Paul
Committee MemberMa, Xiaochao
Committee MemberWan, 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


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