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Dysregulated activation of fetal liver programme in acute liver failure

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 wit...

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Autores principales: Hyun, Jeongeun, Oh, Seh-Hoon, Premont, Richard T, Guy, Cynthia D, Berg, Carl L, Diehl, Anna Mae
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BMJ Publishing Group 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6580749/
https://www.ncbi.nlm.nih.gov/pubmed/30670575
http://dx.doi.org/10.1136/gutjnl-2018-317603
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author Hyun, Jeongeun
Oh, Seh-Hoon
Premont, Richard T
Guy, Cynthia D
Berg, Carl L
Diehl, Anna Mae
author_facet Hyun, Jeongeun
Oh, Seh-Hoon
Premont, Richard T
Guy, Cynthia D
Berg, Carl L
Diehl, Anna Mae
author_sort Hyun, Jeongeun
collection PubMed
description 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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spelling pubmed-65807492019-07-02 Dysregulated activation of fetal liver programme in acute liver failure Hyun, Jeongeun Oh, Seh-Hoon Premont, Richard T Guy, Cynthia D Berg, Carl L Diehl, Anna Mae Gut Hepatology 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. BMJ Publishing Group 2019-06 2019-01-22 /pmc/articles/PMC6580749/ /pubmed/30670575 http://dx.doi.org/10.1136/gutjnl-2018-317603 Text en © Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ. This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.
spellingShingle Hepatology
Hyun, Jeongeun
Oh, Seh-Hoon
Premont, Richard T
Guy, Cynthia D
Berg, Carl L
Diehl, Anna Mae
Dysregulated activation of fetal liver programme in acute liver failure
title Dysregulated activation of fetal liver programme in acute liver failure
title_full Dysregulated activation of fetal liver programme in acute liver failure
title_fullStr Dysregulated activation of fetal liver programme in acute liver failure
title_full_unstemmed Dysregulated activation of fetal liver programme in acute liver failure
title_short Dysregulated activation of fetal liver programme in acute liver failure
title_sort dysregulated activation of fetal liver programme in acute liver failure
topic Hepatology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6580749/
https://www.ncbi.nlm.nih.gov/pubmed/30670575
http://dx.doi.org/10.1136/gutjnl-2018-317603
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