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. 2022 Oct 18;14(20):4365.
doi: 10.3390/nu14204365.

Statin-Induced Geranylgeranyl Pyrophosphate Depletion Promotes Ferroptosis-Related Senescence in Adipose Tissue

Xin Shu  1   2   3   4 , Jiaqi Wu  1   2   3   4 , Tao Zhang  1   2   3   4 , Xiaoyu Ma  1   2   3   4 , Zuoqin Du  1   2   3   4 , Jin Xu  1   2   3   4 , Jingcan You  1   2   3   4 , Liqun Wang  1   2   3   4 , Ni Chen  1   2   3   4 , Mao Luo  1   2   3   4 , Jianbo Wu  1   2   3   4
Affiliations

Statin-Induced Geranylgeranyl Pyrophosphate Depletion Promotes Ferroptosis-Related Senescence in Adipose Tissue

Xin Shu et al. Nutrients. .

Abstract

Statin treatment is accepted to prevent adverse cardiovascular events. However, atorvastatin, an HMG-CoA reductase inhibitor, has been reported to exhibit distinct effects on senescent phenotypes. Whether atorvastatin can induce adipose tissue senescence and the mechanisms involved are unknown. The effects of atorvastatin-induced senescence were examined in mouse adipose tissue explants. Here, we showed that statin initiated higher levels of mRNA related to cellular senescence markers and senescence-associated secretory phenotype (SASP), as well as increased accumulation of the senescence-associated β-galactosidase (SA-β-gal) stain in adipose tissues. Furthermore, we found that the levels of reactive oxygen species (ROS), malondialdehyde (MDA), and Fe2+ were elevated in adipose tissues treated with atorvastatin, accompanied by a decrease in the expression of glutathione (GSH), and glutathione peroxidase 4 (GPX4), indicating an iron-dependent ferroptosis. Atorvastatin-induced was prevented by a selective ferroptosis inhibitor (Fer-1). Moreover, supplementation with geranylgeranyl pyrophosphate (GGPP), a metabolic intermediate, reversed atorvastatin-induced senescence, SASP, and lipid peroxidation in adipose tissue explants. Atorvastatin depleted GGPP production, but not Fer-1. Atorvastatin was able to induce ferroptosis in adipose tissue, which was due to increased ROS and an increase in cellular senescence. Moreover, this effect could be reversed by the supplement of GGPP. Taken together, our results suggest that the induction of ferroptosis contributed to statin-induced cell senescence in adipose tissue.

Keywords: adipose tissue; ferroptosis; obesity; senescence; statin.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Statins induce the onset of senescence in adipose tissue. (A–C). Isolated epidydimal adipose tissues (EAT) were treated with statins (1 μM) for 18 h, as indicated. qPCR analysis of total RNA isolated from EAT for P16 (A), P21 (B), and P53 (C) mRNAs, respectively. Data were normalized to the amount of 18S mRNA and expressed relative to the corresponding control. n = 6 per group. * p < 0.05 vs. control; ** p < 0.05 vs. control; # p < 0.05 vs. control. Data are mean ± SEM. (D–F). EATs were treated with atorvastatin (0, 0.01, 0.1, 1 μM) for 18 h, as indicated. qPCR analysis of total RNA isolated from EAT for P16 (D), P21 (E), and P53 (F) mRNAs, respectively. Data were normalized to the amount of 18S mRNA and expressed relative to the corresponding control. n = 6 per group. * p < 0.05 vs. control, 0.01, 0.1 μM. Data are mean ± SEM. Ator, Atorvastatin. (G,H). Senescence was evaluated in terms of SA-β-galactosidase activity and expressed as the ratio of tissue protein (mg). n = 6 per group. * p < 0.05 vs. control. Data shown as mean ± SEM.
Figure 2
Figure 2
Supplementation of GGPP restores atorvastatin-induced senescence. (A–C). EAT explants were treated with atorvastatin (1 μM) plus supplementation with and without GGPP (50 μM) as indicated. qPCR analysis of total RNA isolated from EAT for P16 (A), P21 (B), and P53 (C) mRNAs, respectively. Data were normalized to the amount of 18S mRNA and expressed relative to the corresponding control. n = 6 per group. * p < 0.05 vs. control. ** p < 0.05 vs. Ator; # p < 0.05 vs. Control; (D–H). The mRNA levels of MCP-1, MMP3, IL-6, PAI-1, CD68, and MMP3 of EAT were quantified by qPCR. * p < 0.05 vs. Control; # p < 0.05 vs. Ator. Data are mean ± SEM. Ator, atorvastatin.
Figure 3
Figure 3
Ferroptosis contributes to atorvastatin-induced senescence in adipose tissue. (A,B). EAT explants were treated with atorvastatin (1 μM) plus supplementation with and without GGPP (50 μM). Representative immunoblot (A) and quantification (B) as indicated. All graphs correspond to the blot and represent densitometric analyses of 3 independent experiments. * p < 0.05 vs. Control; ** p < 0.05 vs. Ator; # p < 0.05 vs. control, Ator, and Ator + GGPP. (C–E). EAT explants were treated with atorvastatin (1 μM) plus ferrostatin-1 (Fer-1, 8 μM) for 18 h, as indicated. qPCR analysis of total RNA isolated from EAT for P16 (C), P21 (D), and P53 (E) mRNAs, respectively. Data were normalized to the amount of 18S mRNA and expressed relative to the corresponding control. n = 6 per group. * p < 0.05 vs. control. ** p < 0.05 vs. Ator; # p < 0.05 vs. Control, Ator, and Ator + Fer-1. (F–H). The mRNA levels of IL-6, PAI-1, and MCP-1 were quantified by qPCR. * p < 0.05 vs. control. ** p < 0.05 vs. Ator; # p < 0.05 vs. Control, Ator, and Ator + Fer-1. (I,J). Senescence was evaluated in terms of SA-β-galactosidase activity treated as indicated and expressed as the ratio of tissue protein (mg). n = 6 per group. * p < 0.05 vs. control. ** p < 0.05 vs. Ator; # p < 0.05 vs. Control, Ator, and Ator + GGPP; # p < 0.05 vs. Control, Ator, and Ator + Fer-1; ## p < 0.05 vs. Control. Data are mean ± SEM. Ator, atorvastatin; Fer-1, ferrostatin-1.
Figure 3
Figure 3
Ferroptosis contributes to atorvastatin-induced senescence in adipose tissue. (A,B). EAT explants were treated with atorvastatin (1 μM) plus supplementation with and without GGPP (50 μM). Representative immunoblot (A) and quantification (B) as indicated. All graphs correspond to the blot and represent densitometric analyses of 3 independent experiments. * p < 0.05 vs. Control; ** p < 0.05 vs. Ator; # p < 0.05 vs. control, Ator, and Ator + GGPP. (C–E). EAT explants were treated with atorvastatin (1 μM) plus ferrostatin-1 (Fer-1, 8 μM) for 18 h, as indicated. qPCR analysis of total RNA isolated from EAT for P16 (C), P21 (D), and P53 (E) mRNAs, respectively. Data were normalized to the amount of 18S mRNA and expressed relative to the corresponding control. n = 6 per group. * p < 0.05 vs. control. ** p < 0.05 vs. Ator; # p < 0.05 vs. Control, Ator, and Ator + Fer-1. (F–H). The mRNA levels of IL-6, PAI-1, and MCP-1 were quantified by qPCR. * p < 0.05 vs. control. ** p < 0.05 vs. Ator; # p < 0.05 vs. Control, Ator, and Ator + Fer-1. (I,J). Senescence was evaluated in terms of SA-β-galactosidase activity treated as indicated and expressed as the ratio of tissue protein (mg). n = 6 per group. * p < 0.05 vs. control. ** p < 0.05 vs. Ator; # p < 0.05 vs. Control, Ator, and Ator + GGPP; # p < 0.05 vs. Control, Ator, and Ator + Fer-1; ## p < 0.05 vs. Control. Data are mean ± SEM. Ator, atorvastatin; Fer-1, ferrostatin-1.
Figure 4
Figure 4
Atorvastatin causes lipid peroxidation in adipose tissue. (A). EAT explants were treated with atorvastatin (1 μM) plus either supplementation with and without GGPP (50 μM) or Fer-1 (8 μM) for 18 h, as indicated. The levels of ROS production in EAT were measured by ROS assay kit following instruction. (B–D). The levels of MDA, GSH, and Fe2+ in EATs were measured by following instructions. Data were expressed relative to the corresponding control. n = 6 per group. * p < 0.05 vs. control. ** p < 0.05 vs. Ator; *# p < 0.05 vs. Control, Ator, and Ator + GGPP; # p < 0.05 vs. Ator; ## p < 0.05 vs. Control, Ator, and Ator + Fer-1. Data are mean ± SEM. Ator, atorvastatin; Fer-1, ferrostatin-1.
Figure 5
Figure 5
Ferroptosis is not involved in atorvastatin-induced GGPP depletion in adipose tissue. EAT explants were treated with atorvastatin (1 μM) plus Fer-1 (8 μM) for 18 h, as indicated. GGPP levels were measured by ELISA following the instruction. Data were expressed relative to the corresponding control. n = 6 per group. * p < 0.05 vs. control. Data are mean ± SEM. Ator, atorvastatin; Fer-1, ferrostatin-1.
Figure 6
Figure 6
Schematic illustration of atorvastatin-induced GGPP depletion promoted ferroptosis-related senescence in adipose tissue. Fer-1, ferrostatin-1; GPX4, glutathione peroxidase 4; GSH, glutathione; ROS, reactive oxygen species.
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Grants and funding

This research was funded by Sichuan Province Science and Technology. Agency Grant (2020YJ0340) and the APC was funded by (2020YJ0340).
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