Egr2 drives the differentiation of Ly6C
Animals
Early Growth Response Protein 2
/ metabolism
Mice
Monocytes
/ metabolism
Cell Differentiation
Macrophages
/ metabolism
Non-alcoholic Fatty Liver Disease
/ metabolism
Liver Cirrhosis
/ metabolism
Mice, Inbred C57BL
Male
Disease Models, Animal
Fatty Acids
/ metabolism
Liver
/ metabolism
Antigens, Ly
Journal
Communications biology
ISSN: 2399-3642
Titre abrégé: Commun Biol
Pays: England
ID NLM: 101719179
Informations de publication
Date de publication:
03 Jun 2024
03 Jun 2024
Historique:
received:
05
10
2023
accepted:
20
05
2024
medline:
4
6
2024
pubmed:
4
6
2024
entrez:
3
6
2024
Statut:
epublish
Résumé
Metabolic dysfunction-associated steatohepatitis (MASH), previously called non-alcoholic steatohepatitis (NASH), is a growing concern worldwide, with liver fibrosis being a critical determinant of its prognosis. Monocyte-derived macrophages have been implicated in MASH-associated liver fibrosis, yet their precise roles and the underlying differentiation mechanisms remain elusive. In this study, we unveil a key orchestrator of this process: long chain saturated fatty acid-Egr2 pathway. Our findings identify the transcription factor Egr2 as the driving force behind monocyte differentiation into hepatic lipid-associated macrophages (hLAMs) within MASH liver. Notably, Egr2-deficiency reroutes monocyte differentiation towards a macrophage subset resembling resident Kupffer cells, hampering hLAM formation. This shift has a profound impact, suppressing the transition from benign steatosis to liver fibrosis, demonstrating the critical pro-fibrotic role played by hLAMs in MASH pathogenesis. Long-chain saturated fatty acids that accumulate in MASH liver emerge as potent inducers of Egr2 expression in macrophages, a process counteracted by unsaturated fatty acids. Furthermore, oral oleic acid administration effectively reduces hLAMs in MASH mice. In conclusion, our work not only elucidates the intricate interplay between saturated fatty acids, Egr2, and monocyte-derived macrophages but also highlights the therapeutic promise of targeting the saturated fatty acid-Egr2 axis in monocytes for MASH management.
Identifiants
pubmed: 38831027
doi: 10.1038/s42003-024-06357-5
pii: 10.1038/s42003-024-06357-5
doi:
Substances chimiques
Early Growth Response Protein 2
0
Egr2 protein, mouse
0
Ly-6C antigen, mouse
0
Fatty Acids
0
Antigens, Ly
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
681Subventions
Organisme : Ministry of Education, Culture, Sports, Science and Technology (MEXT)
ID : 22H05190
Organisme : Ministry of Education, Culture, Sports, Science and Technology (MEXT)
ID : 22H05064
Organisme : Ministry of Education, Culture, Sports, Science and Technology (MEXT)
ID : JPMXP0618217493, JPMXP0622717006, and JPMXP0723833149
Organisme : Japan Society for the Promotion of Science London (JSPS London)
ID : 20H03473
Organisme : Japan Society for the Promotion of Science London (JSPS London)
ID : 21K06877
Organisme : Japan Agency for Medical Research and Development (AMED)
ID : JP18gm1210002
Organisme : Japan Agency for Medical Research and Development (AMED)
ID : JP21gm6210025
Informations de copyright
© 2024. The Author(s).
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