Objective To observe the effect of Urantide on α-SMA and OPN in ApoE ^-/- mice with metabolic-associated fatty liver disease (MAFLD), and to explore its therapeutic effect on liver fibrosis in atherosclerosis (AS) complicated with MAFLD. Methods ApoE ^-/- mice were divided into AS model group, simvastatin group, low -dose, medium -dose, and high-dose Urantide groups. C57BL/6 mice were used as control group. The control group and AS model group were treated with normal saline 20 mg/kg, the simvastatin group was treated with simvastatin 5 mg/kg, and the Urantide group was treated with Urantide 20 mg/kg, 30 mg/kg and 40 mg/kg, respectively. After 14 days of treatment, the pathological changes of liver were observed by HE and oil red O staining. Masson trichrome staining was used to observe the expression of collagen fibers in the liver. The expression and localization of α-SMA in liver were detected by immunohistochemistry. RT-qPCR was used to detect the gene changes of UⅡ/UT system. The expressions of α-SMA, OPN and UⅡ/UT system in liver were detected by Western blotting. Results Compared with the control group, the mice in the AS model group showed liver steatosis, oil red O staining showed a large number of lipid droplets infiltration, collagen fiber deposition in the periosinusitis space, and the expression of α-SMA, OPN, UII and GPR14 protein in the liver increased. UII and GPR14 mRNA levels were increased. After Urantide treatment, the lipid droplets and fatty lesions in the liver were significantly reduced, collagen fibers were reduced, and the expressions of UⅡ/UT system, α-SMA and OPN were significantly decreased. Conclusion Urantide may improve hepatic steatosis in ApoE ^-/- mice by antagonizing the UⅡ/UT system.