Targeting fatty acid metabolism in hepatic macrophages mitigates acetaminophen-induced liver injury and promotes regeneration in mice.

Abstract

BACKGROUND: An overdose of acetaminophen (APAP) can cause severe liver injury and may even lead to death. However, the mechanisms that underlie APAP-induced liver injury (AILI) are not fully understood. The extensive liver necrosis resulting from APAP overdose aggravates the sterile inflammatory response by activating resident macrophages and recruiting various immune cells. Numerous studies have highlighted the crucial role of lipid metabolism in macrophage function. This study investigated fatty acid metabolism in hepatic macrophages and its impact on the progression of AILI. METHODS: We administered APAP intraperitoneally to C57/B6L mice to induce acute liver injury and studied lipid changes in hepatic macrophages. We treated hepacytes with APAP and collected the conditioned medium to stimulate macrophages. Moreover, we generated a myeloid-specific knockout of Fasn mice to validate the role of de novo lipogenesis in macrophages during AILI. RESULTS: We stained liver tissue sections with Bodipy493/503 lipid dye and observed elevated lipid levels in hepatic macrophages after AILI. Mechanistically, HMGB1 released from necrotic hepatocytes increases FASN expression by activating the PI3K/AKT/sterol regulatory element-binding protein-1 (SREBP1) signaling pathway in macrophages. The enhanced de novo lipogenesis increased inflammatory factor expression in macrophages and facilitated their migratory ability. Conversely, myeloid-specific knockout of Fasn reduced the inflammatory response of macrophages and inhibited their chemotaxis in vivo and in vitro. Furthermore, either myeloid-specific knockout of Fasn or treatment with orlistat, a FASN inhibitor, notably improved liver necrosis and accelerated injury resolution following AILI in mice. CONCLUSIONS: Our findings suggest that targeting de novo lipogenesis in hepatic macrophages may represent a novel strategy for treating AILI.