To address the knowledge gap regarding S100A8+ macrophage–derived mediators that induce fat accumulation in hepatocytes, we generated macrophage-specific S100a8-KO mice to study the role of macrophage S100A8 in promoting steatosis after HFD feeding, and we identified the ability of S100A8+ macrophages to alleviate CCN3-induced CD36 suppression as a potential mechanism contributing to hepatocyte fat accumulation. Here, S100A8 is linked to steatosis.