Septin 4 activates PPAR[gamma]/LXR[alpha] signaling by upregulating ABCA1 and ABCG1 expression to inhibit the formation of THP-1 macrophage-derived foam cells

• Published in: Experimental and therapeutic medicine 2021-07, Vol.22 (1)
• Main Authors: Song, Xiaoying, Yan, Guoliang, Wang, Haihui, Lou, Danfei
• Format: Article
• Language: English
• Subjects: Atherosclerosis; Binding proteins; Care and treatment; Cellular signal transduction; Development and progression; Gene expression; Genetic aspects; Health aspects
• ISSN: 1792-0981
• DOI: 10.3892/etm.202U0195

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 [gamma] (PPAR[gamma]) 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 PPAR[gamma] and liver X receptor [alpha] (LXR[alpha]) were also decreased after Septin 4 knockdown. However, Septin 4 overexpression resulted in the opposite results being observed. Additionally, blocking PPAR[gamma] activity using its inhibitor T0070907 or knocking down LXR[alpha] 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 PPAR[gamma]/LXR[alpha] signaling and subsequently enhancing ABCA1/G1 expression. Key words: macrophage, foam cell, atherosclerosis, septin 4, peroxisome proliferator activated [gamma]