ミエロイド細胞のAEG-1/MTDHは、食事誘発性脂肪肝炎における炎症と肝細胞機能不全を駆動する

Astrocyte elevated gene-1/Metadherin (AEG-1/MTDH) plays an important role in regulating lipid metabolism and inflammation in hepatocytes, and promotes metabolic dysfunction-associated steatohepatitis (MASH). Myeloid cells, such as macrophages, play a key role in regulating inflammation. Here we investigated the role of AEG-1 in myeloid cells in regulating high fat/high sugar diet (HF/HSD)-induced MASH. Littermates of myeloid cell-specific AEG-1 knockout mice (AEG-1^ΔMAC) and AEG-1 floxed mice (AEG-1^fl/fl) were fed either control diet (CD) or HF/HSD for 20 weeks. Both male and female AEG-1^ΔMAC mice were significantly protected from MASH development compared to AEG-1^fl/fl mice. In CD-fed mice, spatial transcriptomics (ST) analysis revealed inhibition of hepatic steatosis and development of hepatocellular carcinoma (HCC), and activation of fatty acid β-oxidation (FAO) in the periportal and pericentral hepatocytes of AEG-1^ΔMAC livers. Single cell RNA-sequencing, performed in HF/HSD-fed mice, identified a significant decrease in the total number of Kupffer cells (KC) in AEG-1^ΔMAC vs AEG-1^fl/fl livers. A marked inhibition of inflammation and fibrosis in KC and stellate cells, increased FAO in stellate and endothelial cells, and inhibition of proliferation and invasion in the hepatocytes, especially in pericentral hepatocytes, were observed in AEG-1^ΔMAC liver vs AEG-1^fl/fl liver. Mesenteric fat weight, adipocyte size and inflammation were significantly decreased in HF/HSD-fed AEG-1^ΔMAC mice compared to AEG-1^fl/fl mice. Inhibition of inflammation is a key feature in AEG-1^ΔMAC mice. AEG-1 in myeloid cells regulate gene expression in hepatocytes and other non-parenchymal cells thereby playing an important role in regulating MASH.