Identification of Lineage-Specific Transcription Factors That Prevent Activation of Hepatic Stellate Cells and Promote Fibrosis Resolution.
Animals
Carbon Tetrachloride
/ toxicity
Cell Differentiation
/ drug effects
Cells, Cultured
GATA6 Transcription Factor
/ genetics
Gene Expression Regulation
Gene Knockdown Techniques
Hepatic Stellate Cells
/ drug effects
Humans
Liver Cirrhosis, Experimental
/ chemically induced
Mice
Mice, Transgenic
Myofibroblasts
/ pathology
PPAR gamma
/ agonists
Primary Cell Culture
Proto-Oncogene Protein c-ets-1
/ genetics
Epigenetic Regulation
Inactivation of Fibrogenic Myofibroblasts
Lineage-Determining Transcription Factors
Resolution of Liver Fibrosis
Journal
Gastroenterology
ISSN: 1528-0012
Titre abrégé: Gastroenterology
Pays: United States
ID NLM: 0374630
Informations de publication
Date de publication:
05 2020
05 2020
Historique:
received:
02
05
2019
revised:
07
01
2020
accepted:
13
01
2020
pubmed:
27
1
2020
medline:
21
10
2020
entrez:
27
1
2020
Statut:
ppublish
Résumé
Development of liver fibrosis is associated with activation of quiescent hepatic stellate cells (HSCs) into collagen type I-producing myofibroblasts (activated HSCs). Cessation of liver injury often results in fibrosis resolution and inactivation of activated HSCs/myofibroblasts into a quiescent-like state (inactivated HSCs). We aimed to identify molecular features of phenotypes of HSCs from mice and humans. We performed studies with Lrat Motif enrichment identified E26 transcription-specific transcription factors (ETS) 1, ETS2, GATA4, GATA6, interferon regulatory factor (IRF) 1, and IRF2 transcription factors as regulators of the mouse and human HSC lineage. Small hairpin RNA-knockdown of these transcription factors resulted in increased expression of genes that promote fibrogenesis and inflammation, and loss of HSC phenotype. Disruption of Gata6 or Ets1, or Nf1 or Pparγ (which are regulated by ETS1), increased the severity of CCl Phenotypes of HSCs from humans and mice are regulated by transcription factors, including ETS1, ETS2, GATA4, GATA6, IRF1, and IRF2. Activated mouse and human HSCs can revert to a quiescent-like, inactivated phenotype. We found GATA6 and PPARγ to be required for inactivation of human HSCs and regression of liver fibrosis in mice.
Sections du résumé
BACKGROUND & AIMS
Development of liver fibrosis is associated with activation of quiescent hepatic stellate cells (HSCs) into collagen type I-producing myofibroblasts (activated HSCs). Cessation of liver injury often results in fibrosis resolution and inactivation of activated HSCs/myofibroblasts into a quiescent-like state (inactivated HSCs). We aimed to identify molecular features of phenotypes of HSCs from mice and humans.
METHODS
We performed studies with Lrat
RESULTS
Motif enrichment identified E26 transcription-specific transcription factors (ETS) 1, ETS2, GATA4, GATA6, interferon regulatory factor (IRF) 1, and IRF2 transcription factors as regulators of the mouse and human HSC lineage. Small hairpin RNA-knockdown of these transcription factors resulted in increased expression of genes that promote fibrogenesis and inflammation, and loss of HSC phenotype. Disruption of Gata6 or Ets1, or Nf1 or Pparγ (which are regulated by ETS1), increased the severity of CCl
CONCLUSIONS
Phenotypes of HSCs from humans and mice are regulated by transcription factors, including ETS1, ETS2, GATA4, GATA6, IRF1, and IRF2. Activated mouse and human HSCs can revert to a quiescent-like, inactivated phenotype. We found GATA6 and PPARγ to be required for inactivation of human HSCs and regression of liver fibrosis in mice.
Identifiants
pubmed: 31982409
pii: S0016-5085(20)30117-7
doi: 10.1053/j.gastro.2020.01.027
pmc: PMC7252905
mid: NIHMS1569242
pii:
doi:
Substances chimiques
ETS1 protein, human
0
Ets1 protein, mouse
0
GATA6 Transcription Factor
0
GATA6 protein, human
0
Gata6 protein, mouse
0
PPAR gamma
0
PPARG protein, human
0
Pparg protein, mouse
0
Proto-Oncogene Protein c-ets-1
0
Carbon Tetrachloride
CL2T97X0V0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
1728-1744.e14Subventions
Organisme : NIAAA NIH HHS
ID : U01 AA018663
Pays : United States
Organisme : BLRD VA
ID : I01 BX001991
Pays : United States
Organisme : NIAAA NIH HHS
ID : U01 AA029019
Pays : United States
Organisme : NIDDK NIH HHS
ID : F32 DK009920
Pays : United States
Organisme : NIAAA NIH HHS
ID : R01 AA028550
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA023100
Pays : United States
Organisme : BLRD VA
ID : I01 BX003732
Pays : United States
Organisme : NIAAA NIH HHS
ID : U01 AA022614
Pays : United States
Organisme : BLRD VA
ID : I01 BX003635
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA199376
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK101737
Pays : United States
Organisme : NIDDK NIH HHS
ID : R56 DK088837
Pays : United States
Organisme : NIAID NIH HHS
ID : K99 AI135031
Pays : United States
Organisme : NIAID NIH HHS
ID : R37 AI043477
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK111866
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK099205
Pays : United States
Organisme : NIAAA NIH HHS
ID : P50 AA011999
Pays : United States
Organisme : BLRD VA
ID : I01 BX002213
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI043477
Pays : United States
Informations de copyright
Copyright © 2020 AGA Institute. Published by Elsevier Inc. All rights reserved.
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