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

Song,Xiaoying; Yan,Guoliang; Wang,Haihui; Lou,Danfei

doi:10.3892/etm.2021.10195

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

Authors:
- Xiaoying Song
- Guoliang Yan
- Haihui Wang
- Danfei Lou
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Affiliations: Department of Geriatrics, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200071, P.R. China, Department of Emergency, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200071, P.R. China
Published online on: May 13, 2021 https://doi.org/10.3892/etm.2021.10195
Article Number: 763
Copyright: © Song et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

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.

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