Tung, Hung-Chun
(2022)
THE ROLE OF CYTOCHROME P450 1B1 IN LIVER FIBROSIS AND TREHALOSE METABOLSIM.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
Cytochrome P450 1b1 (Cyp1b1) is a heme-thiolate monooxygenase that metabolizes a variety of endobiotics and xenobiotics. Cyp1b1 is a known transcriptional target of the aryl hydrocarbon receptor (AhR). Accumulating evidence indicates the biochemical role of Cyp1b1 in modulation the link between metabolic pathways and metabolic diseases. Cyp1b1 ablation prevents metabolic diseases, fibrotic diseases, and tumorigenesis in mice. In this dissertation study, I investigated whether and how Cyp1b1 plays a role in hepatic stellate cell (HSC) activation and liver fibrosis. Liver fibrosis is characterized by the accumulation of extracellular matrix (ECM). Activation of the ECM-producing HSC is a key fibrogenic event.
The first part of my dissertation is to determine the role of Cyp1b1 and how it is transcriptionally regulated in the context of liver fibrosis. My results demonstrated that the hepatic expression of Cyp1b1 was elevated in fibrotic human and mouse livers, as well as in activated HSCs. Ablation or pharmacological inhibition of Cyp1b1 by 2,4,3′,5′-tetramethoxystilbene (TMS) attenuated HSC activation. Moreover, Cyp1b1 ablation or treatment with TMS protected mice from liver fibrosis. Mechanistically, the fibrogenic induction of Cyp1b1 was mediated by the transcriptional factor Wilms’ tumor 1 (WT1). The pro-fibrogenic activity of Cyp1b1 in HSCs may have been accounted for by its metabolism of retinoids, the depletion of which is the hallmark of HSC activation.
The second part of my dissertation is to determine the metabolic basis by which Cyp1b1 ablation ameliorates liver fibrosis. Our metabolomic analysis revealed the accumulation of trehalose in Cyp1b1 deficient HSCs, intestine, and blood, likely as a result of the suppression of the trehalose-metabolizing enzyme trehalase in the intestine. Trehalose exhibited potent anti-fibrotic activity and functioned as an autophagy inhibitor specifically in HSCs, which may have accounted for the anti-fibrosis effect of Cyp1b1 inhibition.
My study has uncovered a previously unrecognized endobiotic function of Cyp1b1 in liver fibrosis mediated by organ crosstalk and the metabolite trehalose. Pharmacological inhibition of Cyp1b1 represents a potential strategy for the clinical management of liver fibrosis.
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Details
| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
|
| ETD Committee: |
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| Date: |
8 April 2022 |
| Date Type: |
Publication |
| Defense Date: |
29 March 2022 |
| Approval Date: |
8 April 2022 |
| Submission Date: |
8 April 2022 |
| Access Restriction: |
2 year -- Restrict access to University of Pittsburgh for a period of 2 years. |
| Number of Pages: |
105 |
| 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: |
Liver Fibrosis, Cytochrome P450 1B1, Trehalose |
| Date Deposited: |
08 Apr 2022 13:49 |
| Last Modified: |
08 Apr 2024 05:15 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/42476 |
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