Septin 4 activates PPARγ/LXRα signaling by upregulating ABCA1 and ABCG1 expression to inhibit the formation of THP-1 macrophage-derived foam cells.

Septin 4 is a member of a family of GTP-binding proteins that has been previously reported regulate cytoskeletal organization. In addition, it has been suggested to serve a role in atherosclerosis. Therefore, the present study aimed to investigate the effects of Septin 4 on foam cell formation. THP-1 cells were first exposed to phorbol-12-myristate-13-acetate for differentiation into macrophages before being transformed into foam cells by treatment with oxidized low-density lipoprotein (ox-LDL). Septin 4 expression was then knocked down or overexpressed in THP-1 cells using transfection, whilst peroxisome proliferator activated receptor γ (PPARγ) was also inhibited using its selective antagonist (T0070907) in the presence of Septin 4 overexpression. Oil red staining was used to detect lipid uptake, and total cholesterol (TC), free cholesterol (FC) and ATP binding cassette subfamily A/G member 1 (ABCA1/G1) protein expression were also measured. The results demonstrated that upon ox-LDL stimulation, macrophages that were derived from THP-1 cells transformed into foam cells, where Septin 4 was highly expressed in ox-LDL-induced foam cells. Septin 4 knockdown promoted TC and FC levels, but reduced ABCA1/G1 protein expression. The protein expression levels of PPARγ and liver X receptor α (LXRα) were also decreased after Septin 4 knockdown. However, Septin 4 overexpression resulted in the opposite results being observed. Additionally, blocking PPARγ activity using its inhibitor T0070907 or knocking down LXRα expression using short hairpin RNA reversed the effects of Septin 4 overexpression on foam cell formation and cholesterol handling. In conclusion, Septin 4 may serve an important role in preventing foam cell formation by activating PPARγ/LXRα signaling and subsequently enhancing ABCA1/G1 expression.