PMID- 30695023
OWN - NLM
STAT- MEDLINE
DCOM- 20191104
LR  - 20200309
IS  - 1545-7885 (Electronic)
IS  - 1544-9173 (Print)
IS  - 1544-9173 (Linking)
VI  - 17
IP  - 1
DP  - 2019 Jan
TI  - Insulin resistance disrupts epithelial repair and niche-progenitor Fgf signaling 
      during chronic liver injury.
PG  - e2006972
LID - 10.1371/journal.pbio.2006972 [doi]
LID - e2006972
AB  - Insulin provides important information to tissues about feeding behavior and 
      energy status. Defective insulin signaling is associated with ageing, tissue 
      dysfunction, and impaired wound healing. In the liver, insulin resistance leads 
      to chronic damage and fibrosis, but it is unclear how tissue-repair mechanisms 
      integrate insulin signals to coordinate an appropriate injury response or how 
      they are affected by insulin resistance. In this study, we demonstrate that 
      insulin resistance impairs local cellular crosstalk between the fibrotic stroma 
      and bipotent adult liver progenitor cells (LPCs), whose paracrine interactions 
      promote epithelial repair and tissue remodeling. Using insulin-resistant mice 
      deficient for insulin receptor substrate 2 (Irs2), we highlight dramatic 
      impairment of proregenerative fibroblast growth factor 7 (Fgf7) signaling between 
      stromal niche cells and LPCs during chronic injury. We provide a detailed account 
      of the role played by IRS2 in promoting Fgf7 ligand and receptor (Fgfr2-IIIb) 
      expression by the two cell compartments, and we describe an 
      insulin/IRS2-dependent feed-forward loop capable of sustaining hepatic 
      re-epithelialization by driving FGFR2-IIIb expression. Finally, we shed light on 
      the regulation of IRS2 and FGF7 within the fibrotic stroma and show-using a human 
      coculture system-that IRS2 silencing shifts the equilibrium away from paracrine 
      epithelial repair in favor of fibrogenesis. Hence, we offer a compelling insight 
      into the contribution of insulin resistance to the pathogenesis of chronic liver 
      disease and propose IRS2 as a positive regulator of communication between cell 
      types and the transition between phases of stromal to epithelial repair.
FAU - Manzano-Nunez, Fatima
AU  - Manzano-Nunez F
AD  - CIBERDEM (Centro de Investigacion Biomedica en Red de Diabetes y Enfermedades 
      Metabolicas Asociadas), Madrid, Spain.
AD  - Centro de Investigacion Principe Felipe, Valencia, Spain.
FAU - Arambul-Anthony, Maria Jose
AU  - Arambul-Anthony MJ
AD  - CIBERDEM (Centro de Investigacion Biomedica en Red de Diabetes y Enfermedades 
      Metabolicas Asociadas), Madrid, Spain.
AD  - Centro de Investigacion Principe Felipe, Valencia, Spain.
FAU - Galan Albinana, Amparo
AU  - Galan Albinana A
AD  - Centro de Investigacion Principe Felipe, Valencia, Spain.
FAU - Leal Tassias, Aranzazu
AU  - Leal Tassias A
AD  - Centro de Investigacion Principe Felipe, Valencia, Spain.
FAU - Acosta Umanzor, Carlos
AU  - Acosta Umanzor C
AD  - CIBERDEM (Centro de Investigacion Biomedica en Red de Diabetes y Enfermedades 
      Metabolicas Asociadas), Madrid, Spain.
AD  - Centro de Investigacion Principe Felipe, Valencia, Spain.
FAU - Borreda Gasco, Irene
AU  - Borreda Gasco I
AD  - Instituto Valenciano de Patologia, Universidad Catolica de Valencia San Vicente 
      Martir, Valencia, Spain.
FAU - Herrera, Antonio
AU  - Herrera A
AD  - Centro de Investigacion Principe Felipe, Valencia, Spain.
FAU - Forteza Vila, Jeronimo
AU  - Forteza Vila J
AD  - Centro de Investigacion Principe Felipe, Valencia, Spain.
AD  - Instituto Valenciano de Patologia, Universidad Catolica de Valencia San Vicente 
      Martir, Valencia, Spain.
FAU - Burks, Deborah J
AU  - Burks DJ
AD  - CIBERDEM (Centro de Investigacion Biomedica en Red de Diabetes y Enfermedades 
      Metabolicas Asociadas), Madrid, Spain.
AD  - Centro de Investigacion Principe Felipe, Valencia, Spain.
FAU - Noon, Luke A
AU  - Noon LA
AUID- ORCID: 0000-0002-0502-4322
AD  - CIBERDEM (Centro de Investigacion Biomedica en Red de Diabetes y Enfermedades 
      Metabolicas Asociadas), Madrid, Spain.
AD  - Centro de Investigacion Principe Felipe, Valencia, Spain.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20190129
PL  - United States
TA  - PLoS Biol
JT  - PLoS biology
JID - 101183755
RN  - 0 (FGF7 protein, human)
RN  - 0 (Fgf7 protein, mouse)
RN  - 0 (IRS2 protein, human)
RN  - 0 (Insulin)
RN  - 0 (Insulin Receptor Substrate Proteins)
RN  - 0 (Irs2 protein, mouse)
RN  - 0 (Receptors, Fibroblast Growth Factor)
RN  - 126469-10-1 (Fibroblast Growth Factor 7)
RN  - IY9XDZ35W2 (Glucose)
SB  - IM
MH  - Animals
MH  - Chemical and Drug Induced Liver Injury, Chronic/*metabolism
MH  - Disease Models, Animal
MH  - Epithelial Cells/metabolism
MH  - Fibroblast Growth Factor 7/*metabolism/physiology
MH  - Glucose/metabolism
MH  - Humans
MH  - Insulin/metabolism
MH  - Insulin Receptor Substrate Proteins/genetics/*metabolism/physiology
MH  - Insulin Resistance/physiology
MH  - Liver/metabolism
MH  - Mice
MH  - Receptors, Fibroblast Growth Factor/metabolism
MH  - Signal Transduction/physiology
MH  - Stem Cells/metabolism/physiology
PMC - PMC6368328
COIS- The authors have declared that no competing interests exist.
EDAT- 2019/01/30 06:00
MHDA- 2019/11/05 06:00
PMCR- 2019/01/29
CRDT- 2019/01/30 06:00
PHST- 2018/07/30 00:00 [received]
PHST- 2019/01/08 00:00 [accepted]
PHST- 2019/02/08 00:00 [revised]
PHST- 2019/01/30 06:00 [pubmed]
PHST- 2019/11/05 06:00 [medline]
PHST- 2019/01/30 06:00 [entrez]
PHST- 2019/01/29 00:00 [pmc-release]
AID - pbio.2006972 [pii]
AID - 10.1371/journal.pbio.2006972 [doi]
PST - epublish
SO  - PLoS Biol. 2019 Jan 29;17(1):e2006972. doi: 10.1371/journal.pbio.2006972. 
      eCollection 2019 Jan.