To investigate the effect of Notch-1 signaling on NAFLD and its molecular mechanism.The lipid deposition in liver tissues was detected by oil red O staining. Western blotting was performed to detect the expressions of SREBP1C, SREBP2, LXR, IL-1β, IL-18, NLRP3, Notch-1, NOX2, NOX4, p-PI3K and p-SHP2 in macrophages, and the expressions of ALIX, CD9, IL-1β and SREBP1C in exosomes. Macrophages in the Notch-1MAC-KO group and Notch-1WT group were treated with FFA, and those in the Notch-1WT+FFA group and Notch-1MAC-KO+FFA group were treated with SHP2 inhibitors PHPS1 and Relaxin.It was observed by oil red O staining that lipid deposition in mice with NAFLD was reduced in the Notch-1MAC-KO group. The results of Western blotting showed that the expressions of ALIX, CD9, IL-1β and SREBP1C in macrophage exosomes were significantly lower in the Notch-1MAC-KO group than in the Notch-1WT group. In macrophages, the expressions of SREBP1C, SREBP2, LXR, IL-1β, IL-18, Notch-1, NOX2, NOX4 and p-PI3K significantly decreased, while the expression of p-SHP2 significantly increased in the Notch-1MAC-KO group compared with the Notch-1WT group. The Notch-1MAC-KO+FFA group had significantly decreased expressions of SREBP1C, NLRP3, IL-1β, IL-18, SREBP2, NOX2, NOX4 and p-PI3K and a significantly increased expression of p-SHP2 compared with the Notch-1WT+FFA group. However, the differences in the above proteins were all eliminated after PHPS1 and Relaxin were added.Specific knockout of Notch-1 attenuates NAFLD, and reduces inflammation and lipid deposition in the liver by promoting SHP2 phosphorylation.