Myeloid Endoplasmic Reticulum Resident Chaperone GP96 Facilitates Inflammation and Steatosis in Alcohol-Associated Liver Disease.
Journal
Hepatology communications
ISSN: 2471-254X
Titre abrégé: Hepatol Commun
Pays: United States
ID NLM: 101695860
Informations de publication
Date de publication:
Jul 2021
Jul 2021
Historique:
received:
17
11
2020
revised:
31
01
2021
accepted:
01
03
2021
entrez:
19
7
2021
pubmed:
20
7
2021
medline:
20
7
2021
Statut:
epublish
Résumé
Cellular stress-mediated chaperones are linked to liver macrophage activation and inflammation in alcohol-associated liver disease (ALD). In this study, we investigate the role of endoplasmic reticulum (ER) resident stress chaperone GP96/HSP90B1/GRP94, paralog of the HSP90 family, in ALD pathogenesis. We hypothesize that ER resident chaperone, heat shock protein GP96, plays a crucial role in alcohol-associated liver inflammation and contributes to liver injury. We show high expression of GP96/HSP90B1 and GRP78/HSPA5 in human alcohol-associated hepatitis livers as well as in mouse ALD livers with induction of GP96 prominent in alcohol-exposed macrophages. Myeloid-specific GP96 deficient (M-GP96KO) mice failed to induce alcohol-associated liver injury. Alcohol-fed M-GP96KO mice exhibit significant reduction in steatosis, serum endotoxin, and pro-inflammatory cytokines compared with wild-type mice. Anti-inflammatory cytokines interleukin-10 and transforming growth factor β, as well as activating transcription factor 3 and triggering receptor expressed on myeloid cells 2, markers of restorative macrophages, were higher in alcohol-fed M-GP96KO livers. M-GP96KO mice exhibit protection in a model of endotoxin-mediated liver injury
Identifiants
pubmed: 34278167
doi: 10.1002/hep4.1713
pii: 02009842-202107000-00006
pmc: PMC8279472
doi:
Types de publication
Journal Article
Langues
eng
Pagination
1165-1182Subventions
Organisme : NIA NIH HHS
ID : R01 AG067598
Pays : United States
Organisme : NIAAA NIH HHS
ID : R01 AA017986
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA213290
Pays : United States
Organisme : NCI NIH HHS
ID : P01 CA186866
Pays : United States
Organisme : NIAAA NIH HHS
ID : R01 AA025289
Pays : United States
Informations de copyright
© 2021 The Authors. Hepatology Communications published by Wiley Periodicals LLC on behalf of the American Association for the Study of Liver Diseases.
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