Intercellular Transmission of Hepatic ER Stress in Obesity Disrupts Systemic Metabolism.
connexin 43
diabetes
endoplasmic reticulum stress
gap junctions
insulin resistance
intercellular communication
unfolded protein response
Journal
Cell metabolism
ISSN: 1932-7420
Titre abrégé: Cell Metab
Pays: United States
ID NLM: 101233170
Informations de publication
Date de publication:
02 02 2021
02 02 2021
Historique:
received:
04
01
2019
revised:
30
07
2020
accepted:
12
11
2020
pubmed:
20
12
2020
medline:
30
11
2021
entrez:
19
12
2020
Statut:
ppublish
Résumé
Endoplasmic reticulum stress (ERS) has a pathophysiological role in obesity-associated insulin resistance. Yet, the coordinated tissue response to ERS remains unclear. Increased connexin 43 (Cx43)-mediated intercellular communication has been implicated in tissue-adaptive and -maladaptive response to various chronic stresses. Here, we demonstrate that in hepatocytes, ERS results in increased Cx43 expression and cell-cell coupling. Co-culture of ER-stressed "donor" cells resulted in intercellular transmission of ERS and dysfunction to ERS-naive "recipient" cells ("bystander response"), which could be prevented by genetic or pharmacologic suppression of Cx43. Hepatocytes from obese mice were able to transmit ERS to hepatocytes from lean mice, and mice lacking liver Cx43 were protected from diet-induced ERS, insulin resistance, and hepatosteatosis. Taken together, our results indicate that in obesity, the increased Cx43-mediated cell-cell coupling allows intercellular propagation of ERS. This novel maladaptive response to over-nutrition exacerbates the tissue ERS burden, promoting hepatosteatosis and impairing whole-body glucose metabolism.
Identifiants
pubmed: 33340456
pii: S1550-4131(20)30604-5
doi: 10.1016/j.cmet.2020.11.009
pmc: PMC7858244
mid: NIHMS1655678
pii:
doi:
Substances chimiques
Connexin 43
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
319-333.e6Subventions
Organisme : NIDDK NIH HHS
ID : K08 DK097145
Pays : United States
Organisme : NIDDK NIH HHS
ID : T32 DK007529
Pays : United States
Commentaires et corrections
Type : CommentIn
Type : ErratumIn
Informations de copyright
Copyright © 2020 Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of Interests G.S.H. is an advisory board member of Cell Metabolism.
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