Myeloid AEG-1/MTDH drives inflammation and hepatocellular dysfunction in diet-induced steatohepatitis.

Astrocyte elevated gene-1 (AEG-1)/metadherin 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 a control diet or an HF/HSD for 20 weeks. Both male and female AEG-1(ΔMAC) mice were significantly protected from MASH development compared with AEG-1(fl/fl) mice. In control diet-fed mice, spatial transcriptomics analysis revealed inhibition of hepatic steatosis and development of hepatocellular carcinoma and activation of fatty acid β-oxidation in the periportal and pericentral hepatocytes of AEG-1(ΔMAC) livers. Single-cell RNA-Seq, performed in HF/HSD-fed mice, identified a significant decrease in the total number of Kupffer cells in AEG-1(ΔMAC)versus AEG-1(fl/fl) livers. A marked inhibition of inflammation and fibrosis in Kupffer cells and stellate cells, increased fatty acid β-oxidation 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 versus AEG-1(fl/fl) liver. Mesenteric fat weight, adipocyte size, and inflammation were significantly decreased in HF/HSD-fed AEG-1(ΔMAC) mice compared with 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 nonparenchymal cells, thereby playing an important role in regulating MASH.