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The severity of acute liver failure (ALF) induced by bacterial lipopolysaccharide (LPS) is associated with the hepatic innate immune response. The core circadian molecular clock modulates the innate immune response by controlling rhythmic pathogen recognition by the innate immune system and daily variations in cytokine gene expression. However, the molecular link between circadian genes and the innate immune system has remained unclear. Here, we showed that mice lacking the clock gene  Per1  (Period1) are more susceptible to LPS/ d -galactosamine (LPS/GalN)-induced macrophage-dependent ALF compared with wild-type (WT) mice.  Per1  deletion caused a remarkable increase in the number of Kupffer cells (KCs) in the liver, resulting in an elevation of the levels of pro-inflammatory cytokines after LPS treatment. Loss of  Per1  had no effect on the proliferation or apoptosis of macrophages; however, it enhanced the recruitment of macrophages, which was associated with an increase in CC chemokine receptor 2 ( Ccr2 ) expression levels in monocytes/macrophages. Deletion of  Ccr2  rescued  d -GalN/LPS-induced liver injury in  Per1  −/−  mice. We demonstrated that the upregulation of  Ccr2  expression by  Per1  deletion could be reversed by the synthetic peroxisome proliferator-activated receptor gamma (PPAR- γ ) antagonist GW9662. Further analysis indicated that PER1 binds to PPAR- γ  on the  Ccr2  promoter and enhanced the inhibitory effect of PPAR- γ  on  Ccr2  expression. These results reveal that  Per1  reduces hepatic macrophage recruitment through interaction with PPAR- γ  and prevents an excessive innate immune response in endotoxin-induced liver injury.

PER1 prevents excessive innate immune response during endotoxin-induced liver injury through regulation of macrophage recruitment in mice