| Autor: |
Jung Seok Hwang, Eunsu Kim, Hyuk Gyoon Lee, Won Jin Lee, Jun Pil Won, Jinwoo Hur, Junichi Fujii, Han Geuk Seo |
| Jazyk: |
angličtina |
| Rok vydání: |
2021 |
| Předmět: |
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| Zdroj: |
Biomedicine & Pharmacotherapy, Vol 143, Iss , Pp 112223- (2021) |
| Druh dokumentu: |
article |
| ISSN: |
0753-3322 |
| DOI: |
10.1016/j.biopha.2021.112223 |
| Popis: |
Ferroptosis is a recently recognized process of cell death characterized by accumulation of iron-dependent lipid peroxides. Herein, we demonstrate that peroxisome proliferator-activated receptor δ (PPARδ) inhibits ferroptosis of mouse embryonic fibroblasts (MEFs) derived from cysteine/glutamate transporter (xCT)-knockout mice. Activation of PPARδ by the specific ligand GW501516 led to a dose-dependent decrease in ferroptotic cell death triggered by xCT deficiency, along with decreased levels of intracellular iron accumulation and lipid peroxidation. These effects of GW501516 were abolished by PPARδ-targeting small interfering RNA (siRNA) and the PPARδ inhibitor GSK0660, indicating that PPARδ inhibits xCT deficiency-induced ferroptosis. In addition, GW501516-activated PPARδ time- and dose-dependently upregulated catalase expression at both the mRNA and protein levels. This PPARδ-mediated upregulation of catalase was markedly attenuated in cells treated with PPARδ-targeting siRNA and GSK0660, indicating that expression of catalase is dependent on PPARδ. Consistently, the effects of GW501516 on ferroptosis of xCT-deficient MEFs were counteracted in the presence of 3-amino-1,2,4-triazole, a specific inhibitor of catalase, suggesting that catalase is essential for the effect of PPARδ on ferroptosis triggered by xCT deficiency. GW501516-activated PPARδ stabilized peroxisomes through catalase upregulation by targeting peroxisomal hydrogen peroxide-mediated lysosomal rupture, which led to ferroptosis of xCT-deficient MEFs. Collectively, these results demonstrate that PPARδ modulates ferroptotic signals in xCT-deficient MEFs by regulating catalase expression. |
| Databáze: |
Directory of Open Access Journals |
| Externí odkaz: |
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