Kim, Minwook
(2023)
The Role of PPARα in Liver Progenitor Cell-Mediated Liver Regeneration.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
Regeneration of the liver, which is remarkably regenerative compared to other organs, depends on two distinct mechanisms: (1) proliferation of pre-existing hepatocytes; and (2) cell fate conversion into parenchymal cells. Since the hepatocytes have a high proliferative, the proliferation of pre-existing hepatocytes mainly contributes to maintaining hepatic homeostasis and restoring hepatocyte loss by various injuries. However, long-term or severe damage to hepatocytes can cause the impairment of their proliferative capacity, resulting in liver failure. Unfortunately, liver transplantation is the only treatment option for liver failure; moreover, since there is a shortage of donor livers and a declining quality of donated livers, 15% of listed patients die while awaiting a graft. Therefore, an alternative therapeutic strategy for end-stage liver disease must be developed. When hepatocytes are incapable of proliferation under chronic injury, the liver co-opts the differentiation of liver progenitor cells (LPCs) into hepatocytes to restore functional hepatocytes. This LPC-mediated liver regeneration is considered one of the potential targets for alternative therapy in liver failure. However, the mechanisms by which LPCs differentiate into hepatocytes remain largely unknown. Therefore, we try to elucidate the underlying mechanism and find factors that can promote LPC-mediated liver regeneration.
To study LPC-mediated liver regeneration, I used oncogene-overexpressing transgenic zebrafish Tg(fabp10a:pt-β-catenin) liver injury model. In a previous study, we discovered that the expression of a constitutively active form of β-catenin in the liver induces the dedifferentiation of hepatocytes and biliary epithelial cells (BECs) into LPCs. This is followed by LPCs differentiating into hepatocytes. This hepatocyte-specific oncogene overexpression model allows us to identify compounds or genes that can accelerate LPC-mediated liver regeneration. LPCs are abundant in the liver from 12/13 to 14/15 days post-fertilization (dpf); thus, candidate compounds were applied over this time window.
In this study, I found that the PPARα agonist, GW7647, enhanced the expression of hepatocyte markers and the molecular features of mature hepatocytes during LPC-mediated liver regeneration. Mechanistically, PPARα activation suppressed the YAP signaling pathway, which plays an essential role in biliary formation. The phenotypes resulting from GW7647 treatment were rescued by expressing a constitutively active form of Yap1. Moreover, we found that the treatment with the Tead inhibitor K-975 phenocopied the effect of GW7647 treatment on LPC differentiation. Conclusively, PPARα activation in the Tg(fabp10a:pt-β-catenin) model promotes LPC differentiation into hepatocytes by suppressing YAP signaling. Finally, we reveal that suppression of YAP signaling is sufficient to promote LPC-to-hepatocyte differentiation.
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| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
|
| ETD Committee: |
|
| Date: |
4 October 2023 |
| Date Type: |
Publication |
| Defense Date: |
11 April 2023 |
| Approval Date: |
4 October 2023 |
| Submission Date: |
6 May 2023 |
| Access Restriction: |
1 year -- Restrict access to University of Pittsburgh for a period of 1 year. |
| Number of Pages: |
171 |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
School of Medicine > Developmental Biology |
| Degree: |
PhD - Doctor of Philosophy |
| Thesis Type: |
Doctoral Dissertation |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
liver regeneration, PPAR, YAP, liver progenitor cell |
| Date Deposited: |
04 Oct 2023 16:19 |
| Last Modified: |
04 Oct 2023 16:19 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/44237 |
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