PMID- 37880271
OWN - NLM
STAT- MEDLINE
DCOM- 20231113
LR  - 20240210
IS  - 2045-2322 (Electronic)
IS  - 2045-2322 (Linking)
VI  - 13
IP  - 1
DP  - 2023 Oct 25
TI  - PPARalpha activation promotes liver progenitor cell-mediated liver regeneration by 
      suppressing YAP signaling in zebrafish.
PG  - 18312
LID - 10.1038/s41598-023-44935-5 [doi]
LID - 18312
AB  - Despite the robust regenerative capacity of the liver, prolonged and severe liver 
      damage impairs liver regeneration, leading to liver failure. Since the liver 
      co-opts the differentiation of liver progenitor cells (LPCs) into hepatocytes to 
      restore functional hepatocytes, augmenting LPC-mediated liver regeneration may be 
      beneficial to patients with chronic liver diseases. However, the molecular 
      mechanisms underlying LPC-to-hepatocyte differentiation have remained largely 
      unknown. Using the zebrafish model of LPC-mediated liver regeneration, 
      Tg(fabp10a:pt-beta-catenin), we present that peroxisome proliferator-activated 
      receptor-alpha (PPARalpha) activation augments LPC-to-hepatocyte differentiation. We 
      found that treating Tg(fabp10a:pt-beta-catenin) larvae with GW7647, a potent PPARalpha 
      agonist, enhanced the expression of hepatocyte markers and simultaneously reduced 
      the expression of biliary epithelial cell (BEC)/LPC markers in the regenerating 
      livers, indicating enhanced LPC-to-hepatocyte differentiation. Mechanistically, 
      PPARalpha activation augments the differentiation by suppressing YAP signaling. The 
      differentiation phenotypes resulting from GW7647 treatment were rescued by 
      expressing a constitutively active form of Yap1. Moreover, we found that 
      suppression of YAP signaling was sufficient to promote LPC-to-hepatocyte 
      differentiation. Treating Tg(fabp10a:pt-beta-catenin) larvae with the TEAD inhibitor 
      K-975, which suppresses YAP signaling, phenocopied the effect of GW7647 on LPC 
      differentiation. Altogether, our findings provide insights into augmenting 
      LPC-mediated liver regeneration as a regenerative therapy for chronic liver 
      diseases.
CI  - (c) 2023. Springer Nature Limited.
FAU - Kim, Minwook
AU  - Kim M
AD  - Department of Developmental Biology, McGowan Institute for Regenerative Medicine, 
      Pittsburgh Liver Research Center, University of Pittsburgh, 3501 5th Ave. #5063, 
      Pittsburgh, PA, 15260, USA.
FAU - So, Juhoon
AU  - So J
AD  - Department of Developmental Biology, McGowan Institute for Regenerative Medicine, 
      Pittsburgh Liver Research Center, University of Pittsburgh, 3501 5th Ave. #5063, 
      Pittsburgh, PA, 15260, USA.
FAU - Shin, Donghun
AU  - Shin D
AD  - Department of Developmental Biology, McGowan Institute for Regenerative Medicine, 
      Pittsburgh Liver Research Center, University of Pittsburgh, 3501 5th Ave. #5063, 
      Pittsburgh, PA, 15260, USA. donghuns@pitt.edu.
LA  - eng
GR  - R01 DK101426/DK/NIDDK NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20231025
PL  - England
TA  - Sci Rep
JT  - Scientific reports
JID - 101563288
RN  - 0 (beta Catenin)
RN  - 0 (GW 7647)
RN  - 0 (PPAR alpha)
RN  - 0 (Yes-associated protein (yap), zebrafish)
RN  - 0 (YAP-Signaling Proteins)
SB  - IM
MH  - Animals
MH  - beta Catenin/metabolism
MH  - Cell Proliferation
MH  - Hepatocytes/metabolism
MH  - Liver/metabolism
MH  - *Liver Diseases/metabolism
MH  - Liver Regeneration/physiology
MH  - *PPAR alpha/metabolism
MH  - Stem Cells/metabolism
MH  - *Zebrafish/genetics
MH  - *YAP-Signaling Proteins
PMC - PMC10600117
COIS- The authors declare no competing interests.
EDAT- 2023/10/26 00:42
MHDA- 2023/10/27 06:42
PMCR- 2023/10/25
CRDT- 2023/10/25 23:23
PHST- 2023/06/13 00:00 [received]
PHST- 2023/10/13 00:00 [accepted]
PHST- 2023/10/27 06:42 [medline]
PHST- 2023/10/26 00:42 [pubmed]
PHST- 2023/10/25 23:23 [entrez]
PHST- 2023/10/25 00:00 [pmc-release]
AID - 10.1038/s41598-023-44935-5 [pii]
AID - 44935 [pii]
AID - 10.1038/s41598-023-44935-5 [doi]
PST - epublish
SO  - Sci Rep. 2023 Oct 25;13(1):18312. doi: 10.1038/s41598-023-44935-5.