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Dysregulated activation of fetal liver programme in acute liver failure.

Publication ,  Journal Article
Hyun, J; Oh, S-H; Premont, RT; Guy, CD; Berg, CL; Diehl, AM
Published in: Gut
June 2019

OBJECTIVE: Uncertainty about acute liver failure (ALF) pathogenesis limits therapy. We postulate that ALF results from excessive reactivation of a fetal liver programme that is induced in hepatocytes when acutely injured livers regenerate. To evaluate this hypothesis, we focused on two molecules with known oncofetal properties in the liver, Yes-associated protein-1 (YAP1) and Insulin-like growth factor-2 RNA-binding protein-3 (IGF2BP3). DESIGN: We compared normal liver with explanted livers of patients with ALF to determine if YAP1 and IGF2BP3 were induced; assessed whether these factors are upregulated when murine livers regenerate; determined if YAP1 and IGF2BP3 cooperate to activate the fetal programme in adult hepatocytes; and identified upstream signals that control these factors and thereby hepatocyte maturity during recovery from liver injury. RESULTS: Livers of patients with ALF were massively enriched with hepatocytes expressing IGF2BP3, YAP1 and other fetal markers. Less extensive, transient accumulation of similar fetal-like cells that were proliferative and capable of anchorage-independent growth occurred in mouse livers that were regenerating after acute injury. Fetal reprogramming of hepatocytes was YAP1-dependent and involved YAP1-driven reciprocal modulation of let7 microRNAs and IGF2BP3, factors that negatively regulate each other to control fate decisions in fetal cells. Directly manipulating IGF2BP3 expression controlled the fetal-like phenotype regardless of YAP1 activity, proving that IGF2BP3 is the proximal mediator of this YAP1-directed fate. CONCLUSION: After acute liver injury, hepatocytes are reprogrammed to fetal-like cells by a YAP1-dependent mechanism that differentially regulates let7 and IGF2BP3, identifying novel therapeutic targets for ALF.

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Published In

Gut

DOI

EISSN

1468-3288

Publication Date

June 2019

Volume

68

Issue

6

Start / End Page

1076 / 1087

Location

England

Related Subject Headings

  • YAP-Signaling Proteins
  • Up-Regulation
  • Ubiquitin-Protein Ligases
  • Transcription Factors
  • Reference Values
  • Real-Time Polymerase Chain Reaction
  • Phosphoproteins
  • MicroRNAs
  • Mice
  • Male
 

Citation

APA
Chicago
ICMJE
MLA
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Hyun, J., Oh, S.-H., Premont, R. T., Guy, C. D., Berg, C. L., & Diehl, A. M. (2019). Dysregulated activation of fetal liver programme in acute liver failure. Gut, 68(6), 1076–1087. https://doi.org/10.1136/gutjnl-2018-317603
Hyun, Jeongeun, Seh-Hoon Oh, Richard T. Premont, Cynthia D. Guy, Carl L. Berg, and Anna Mae Diehl. “Dysregulated activation of fetal liver programme in acute liver failure.Gut 68, no. 6 (June 2019): 1076–87. https://doi.org/10.1136/gutjnl-2018-317603.
Hyun J, Oh S-H, Premont RT, Guy CD, Berg CL, Diehl AM. Dysregulated activation of fetal liver programme in acute liver failure. Gut. 2019 Jun;68(6):1076–87.
Hyun, Jeongeun, et al. “Dysregulated activation of fetal liver programme in acute liver failure.Gut, vol. 68, no. 6, June 2019, pp. 1076–87. Pubmed, doi:10.1136/gutjnl-2018-317603.
Hyun J, Oh S-H, Premont RT, Guy CD, Berg CL, Diehl AM. Dysregulated activation of fetal liver programme in acute liver failure. Gut. 2019 Jun;68(6):1076–1087.

Published In

Gut

DOI

EISSN

1468-3288

Publication Date

June 2019

Volume

68

Issue

6

Start / End Page

1076 / 1087

Location

England

Related Subject Headings

  • YAP-Signaling Proteins
  • Up-Regulation
  • Ubiquitin-Protein Ligases
  • Transcription Factors
  • Reference Values
  • Real-Time Polymerase Chain Reaction
  • Phosphoproteins
  • MicroRNAs
  • Mice
  • Male