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

## TL;DR

This study shows that removing AEG-1 in myeloid cells reduces liver inflammation and disease in mice fed a high-fat/sugar diet.

## Contribution

The novel finding is that myeloid AEG-1 regulates MASH by modulating inflammation and metabolism in liver cells.

## Key findings

- AEG-1ΔMAC mice were protected from MASH compared to controls.
- AEG-1ΔMAC mice showed reduced inflammation, fibrosis, and improved fatty acid oxidation in liver cells.
- Mesenteric fat and inflammation were reduced in AEG-1ΔMAC mice.

## Abstract

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-1ΔMAC) and AEG-1 floxed mice (AEG-1fl/fl) were fed either a control diet or an HF/HSD for 20 weeks. Both male and female AEG-1ΔMAC mice were significantly protected from MASH development compared with AEG-1fl/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-1ΔMAC livers. Single-cell RNA-Seq, performed in HF/HSD-fed mice, identified a significant decrease in the total number of Kupffer cells in AEG-1ΔMACversus AEG-1fl/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-1ΔMAC liver versus AEG-1fl/fl liver. Mesenteric fat weight, adipocyte size, and inflammation were significantly decreased in HF/HSD-fed AEG-1ΔMAC mice compared with AEG-1fl/fl mice. Inhibition of inflammation is a key feature in AEG-1ΔMAC mice. AEG-1 in myeloid cells regulate gene expression in hepatocytes and other nonparenchymal cells, thereby playing an important role in regulating MASH.