Link to the University of Pittsburgh Homepage
Link to the University Library System Homepage Link to the Contact Us Form

The Role of PPARα in Liver Progenitor Cell-Mediated Liver Regeneration

Kim, Minwook (2023) The Role of PPARα in Liver Progenitor Cell-Mediated Liver Regeneration. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

[img] PDF
Restricted to University of Pittsburgh users only until 4 October 2024.

Download (42MB) | Request a Copy


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.


Social Networking:
Share |


Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Kim, Minwookminwook@pitt.eduminwook0000-0002-0093-4562
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Thesis AdvisorShin, Donghundonghuns@pitt.edudonghuns
Committee ChairTsang, Michaeltsang@pitt.edutsang
Hukriede, Neilhukriede@pitt.eduhukriede
Monga, Satdarshan P. S.smonga@pitt.edusmonga
Duncan, Andrew W.duncana@pitt.eduduncana
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


Monthly Views for the past 3 years

Plum Analytics

Actions (login required)

View Item View Item