Myeloid-specific ablation of Basp1 ameliorates diet-induced NASH in mice by attenuating pro-inflammatory signaling.
Journal
Hepatology (Baltimore, Md.)
ISSN: 1527-3350
Titre abrégé: Hepatology
Pays: United States
ID NLM: 8302946
Informations de publication
Date de publication:
17 Jul 2023
17 Jul 2023
Historique:
received:
03
04
2023
accepted:
06
07
2023
pubmed:
28
7
2023
medline:
28
7
2023
entrez:
28
7
2023
Statut:
aheadofprint
Résumé
NASH represents a severe stage of fatty liver disease characterized by hepatocyte injury, inflammation, and liver fibrosis. Myeloid-derived innate immune cells, such as macrophages and dendritic cells, play an important role in host defense and disease pathogenesis. Despite this, the nature of transcriptomic reprogramming of myeloid cells in NASH liver and its contribution to disease progression remain incompletely defined. In this study, we performed bulk and single-cell RNA sequencing (sc-RNA seq) analysis to delineate the landscape of macrophage and dendritic cell transcriptomes in healthy and NASH livers. Our analysis uncovered cell type-specific patterns of transcriptomic reprogramming on diet-induced NASH. We identified brain-abundant membrane-attached signal protein 1 (Basp1) as a myeloid-enriched gene that is markedly induced in mouse and human NASH liver. Myeloid-specific inactivation of Basp1 attenuates the severity of diet-induced NASH pathologies, as shown by reduced hepatocyte injury and liver fibrosis in mice. Mechanistically, cultured macrophages lacking Basp1 exhibited a diminished response to pro-inflammatory stimuli, impaired NLRP3 inflammasome activation, and reduced cytokine secretion. Together, these findings uncover Basp1 as a critical regulator of myeloid inflammatory signaling that underlies NASH pathogenesis.
Sections du résumé
BACKGROUND AND AIMS
OBJECTIVE
NASH represents a severe stage of fatty liver disease characterized by hepatocyte injury, inflammation, and liver fibrosis. Myeloid-derived innate immune cells, such as macrophages and dendritic cells, play an important role in host defense and disease pathogenesis. Despite this, the nature of transcriptomic reprogramming of myeloid cells in NASH liver and its contribution to disease progression remain incompletely defined.
APPROACH AND RESULTS
RESULTS
In this study, we performed bulk and single-cell RNA sequencing (sc-RNA seq) analysis to delineate the landscape of macrophage and dendritic cell transcriptomes in healthy and NASH livers. Our analysis uncovered cell type-specific patterns of transcriptomic reprogramming on diet-induced NASH. We identified brain-abundant membrane-attached signal protein 1 (Basp1) as a myeloid-enriched gene that is markedly induced in mouse and human NASH liver. Myeloid-specific inactivation of Basp1 attenuates the severity of diet-induced NASH pathologies, as shown by reduced hepatocyte injury and liver fibrosis in mice. Mechanistically, cultured macrophages lacking Basp1 exhibited a diminished response to pro-inflammatory stimuli, impaired NLRP3 inflammasome activation, and reduced cytokine secretion.
CONCLUSIONS
CONCLUSIONS
Together, these findings uncover Basp1 as a critical regulator of myeloid inflammatory signaling that underlies NASH pathogenesis.
Identifiants
pubmed: 37505219
doi: 10.1097/HEP.0000000000000537
pii: 01515467-990000000-00514
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Informations de copyright
Copyright © 2023 American Association for the Study of Liver Diseases.
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