CD163 Expression Protects Against Early Hepatic Steatosis in Western Diet-Fed Male Mice

Background and Aims: Sustained and excessive consumption of dietary lipids and sugars can lead to hepatic steatosis triggering metabolic dysfunction–associated steatohepatitis (MASH) characterized by inflammation and hepatocellular damage. The activation of macrophages is suggested to play an important role in the pathogenesis of MASH. Liver macrophages have a high expression of the macrophage-specific scavenger receptor CD163, but during MASH development CD163 undergoes increased shedding and downregulated expression in the liver. In this study, we investigate the relation between the expression of CD163 and early hepatic steatosis in mice. Methods: The time-dependent relation between steatosis and CD163 expression was evaluated by staining of liver specimens from male mice after 0, 5, 15, or 25 weeks of Western diet (WD) feeding. To evaluate the impact of CD163 on the early development of hepatic steatosis, we compared CD163 knockout mice and wild-type littermates fed on WD or chow diet for 8 weeks. Besides staining of liver specimens, plasma cytokines were measured, the transcriptome was analyzed by bulk RNA sequencing and liver macrophages were evaluated by flow cytometry. Results: CD163 expression decreased in parallel to the development of hepatic steatosis in WD-fed mice. WD-fed CD163 knockout mice developed more pronounced hepatic steatosis compared to CD163 wild-type littermates after 8 weeks; however, the number of macrophages, systemic cytokine levels, and transcriptome were unaffected by the genotype. Conclusion: A protective role (direct or indirect) of CD163 on early development of hepatic steatosis was indicated by the finding that the severity of steatosis was significantly stronger in CD163 knockout mice. Furthermore, it underlines the importance of macrophages in lipid-driven liver disease.