Atherosclerosis is a chronic inflammatory disease, which is thought to be one of the most common causes of death globally. The functions of macrophage in the development of atherosclerosis inflammation still get more attention. Although lipopolysaccharide (LPS) can trigger inflammation in atherosclerosis, how LPS promotes atherogenesis through acting on macrophage is not very clear. Here, we study the role of adipophilin in LPS-induced inflammation. After RAW264.7 cells were treated with LPS of different concentrations, the protein level of adipophilin was increased dose-dependently, and cells treated with LPS for various time were observed the highest levels of TNF-α, MCP-1, and IL-6 at 12 h. In addition, inhibited extracellular signal-regulated kinase (ERK)-1/2 presented lower levels of adipophilin, peroxisome proliferator-activated receptor gamma (PPARγ), TNF-α, MCP-1, as well as IL-6. But inhibited PPARγ, the levels of adipophilin, TNF-α, MCP-1, and IL-6 were significantly augmented. Moreover, after silence adipophilin, the ERK1/2 activity and protein level of PPARγ were not influenced, whereas the levels of TNF-α, MCP-1, and IL-6 were significantly reduced. LPS can promote the expression of adipophilin through ERK1/2-PPARγ pathway, whereby it enhances the secretion levels of TNF-α, MCP-1, and IL-6.