Wang, Jingyuan
(2024)
Cell Type-specific effects of Liver X Receptor (LXR) and Estrogen Sulfotransferase (EST) on T-cell Mediated Autoimmune Hepatitis (AIH).
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
AIH is a chronic liver disease in which the immune system attacks the liver cells, causing inflammation and liver damage. Long-term and uncontrolled AIH leads to progressive liver fibrosis and cirrhosis. However, the pathological mechanism of AIH remains elusive and there are no effective therapies except for the use of nonspecific immunosuppressive agents such as glucocorticoids. Liver X receptors (LXR), including the α and β isoforms, are nuclear receptors with pivotal roles in the transcriptional control of lipid metabolism. LXRs are previously known for their controversial effects on the development of immune-related diseases, but the specific role of LXRs in the pathogenesis of AIH has not been sufficiently explored. Estrogen sulfotransferase (EST or SULT1E1), a target gene of LXRs, is a phase II conjugating enzyme that catalyzes the transformation of an unconjugated estrogen into a sulfated estrogen, which makes estrogen inactive. Previous work from our lab demonstrated that Est is inducible and functional in several inflammation diseases, including liver ischemia and reperfusion (I/R) injury, sepsis-induced inflammatory response, hemorrhagic shock-induced lung injury, and I/R-induced acute kidney injury. However, the possible mechanisms and roles of EST in AIH remain unknown. In this dissertation study, I studied the cell type-specific effects of LXRs and EST on Concanavalin A-induced mouse AIH model. My results demonstrated that (1) Activation of LXRα sensitizes mice to ConA-induced AIH in iNKT cells and IFN-γ dependent manner. Pharmacological inhibition of LXRα may represent an effective approach to manage AIH in the clinic. (2) Hepatocyte Est is required for the sensitivity of female mice to ConA-induced AIH in an estrogen-independent manner. Mechanistically, Est ablation may have protected female mice from ConA-induced AIH by upregulating lipocalin 2 (Lcn2). Pharmacological inhibition of Est might be a potential strategy for the treatment of AIH. In summary, my dissertation research has uncovered the cell type-specific effects of LXRs and EST in AIH.
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Details
| Item Type: |
University of Pittsburgh ETD
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| Status: |
Unpublished |
| Creators/Authors: |
|
| ETD Committee: |
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| Date: |
23 July 2024 |
| Date Type: |
Publication |
| Defense Date: |
29 January 2024 |
| Approval Date: |
23 July 2024 |
| Submission Date: |
27 June 2024 |
| Access Restriction: |
No restriction; Release the ETD for access worldwide immediately. |
| Number of Pages: |
114 |
| 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: |
Autoimmune Hepatitis, Liver X Receptor, Estrogen Sulfotransferase, Concanavalin A |
| Date Deposited: |
23 Jul 2024 16:39 |
| Last Modified: |
23 Jul 2024 16:39 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/46637 |
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