| RRC ID |
86954
|
| 著者 |
Iwata A, Maruyama J, Natsuki S, Nishiyama A, Tamura T, Tanaka M, Shichino S, Seki T, Komai T, Okamura T, Fujio K, Tanaka M, Asano K.
|
| タイトル |
Egr2 drives the differentiation of Ly6Chi monocytes into fibrosis-promoting macrophages in metabolic dysfunction-associated steatohepatitis in mice.
|
| ジャーナル |
Commun Biol
|
| Abstract |
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.
|
| 巻・号 |
7(1)
|
| ページ |
681
|
| 公開日 |
2024-6-3
|
| DOI |
10.1038/s42003-024-06357-5
|
| PII |
10.1038/s42003-024-06357-5
|
| PMID |
38831027
|
| PMC |
PMC11148031
|
| MeSH |
Animals
Antigens, Ly
Cell Differentiation*
Disease Models, Animal
Early Growth Response Protein 2* / genetics
Early Growth Response Protein 2* / metabolism
Fatty Acids / metabolism
Liver / metabolism
Liver / pathology
Liver Cirrhosis* / etiology
Liver Cirrhosis* / genetics
Liver Cirrhosis* / metabolism
Liver Cirrhosis* / pathology
Macrophages* / metabolism
Male
Mice
Mice, Inbred C57BL
Monocytes* / metabolism
Non-alcoholic Fatty Liver Disease* / etiology
Non-alcoholic Fatty Liver Disease* / metabolism
Non-alcoholic Fatty Liver Disease* / pathology
|
| リソース情報 |
| 実験動物マウス |
RBRC02302 |
