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

Authors :
Shu, Xin
Wu, Jiaqi
Zhang, Tao
Ma, Xiaoyu
Du, Zuoqin
Xu, Jin
You, Jingcan
Wang, Liqun
Chen, Ni
Luo, Mao
Wu, Jianbo
Source :
Nutrients; Oct2022, Vol. 14 Issue 20, p4365-N.PAG, 12p
Publication Year :
2022

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 Fe<superscript>2+</superscript> 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. [ABSTRACT FROM AUTHOR]

Details

Language :
English
ISSN :
20726643
Volume :
14
Issue :
20
Database :
Complementary Index
Journal :
Nutrients
Publication Type :
Academic Journal
Accession number :
159911306
Full Text :
https://doi.org/10.3390/nu14204365