1. Egr2 drives the differentiation of Ly6C hi monocytes into fibrosis-promoting macrophages in metabolic dysfunction-associated steatohepatitis in mice.
- Author
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Iwata A, Maruyama J, Natsuki S, Nishiyama A, Tamura T, Tanaka M, Shichino S, Seki T, Komai T, Okamura T, Fujio K, Tanaka M, and Asano K
- Subjects
- Animals, Mice, Mice, Inbred C57BL, Male, Disease Models, Animal, Fatty Acids metabolism, Liver metabolism, Liver pathology, Antigens, Ly, Early Growth Response Protein 2 metabolism, Early Growth Response Protein 2 genetics, Monocytes metabolism, Cell Differentiation, Macrophages metabolism, Non-alcoholic Fatty Liver Disease metabolism, Non-alcoholic Fatty Liver Disease pathology, Non-alcoholic Fatty Liver Disease etiology, Liver Cirrhosis metabolism, Liver Cirrhosis pathology, Liver Cirrhosis etiology, Liver Cirrhosis genetics
- 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., (© 2024. The Author(s).)
- Published
- 2024
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