In summary, we found that the increased DKK1 is a key factor for hepatic steatosis in HFD-induced NAFLD mice model, which mainly relies on the activation of ERK-PPARγ-CD36 signaling to increase fatty acid uptake and steatosis; on the other hand, DKK1 activates the JNK phosphorylation, resulting in insulin resistance. Here, DKK1 is linked to fatty liver disease.