IMR Press / FBL / Volume 27 / Issue 7 / DOI: 10.31083/j.fbl2707214
Open Access Original Research
Fenofibrate Attenuates Radiation-Induced Oxidative Damage to the Skin through Fatty Acid Binding Protein 4 (FABP4)
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1 Department of Gynecology and Obstetrics, Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, West China Second University Hospital, Sichuan University, 610041 Chengdu, Sichuan, China
2 State Key Lab of Radiation Medicine and Protection, School of Radiation Medicine and Protection, Medical College of Soochow University, 215123 Suzhou, Jiangsu, China
3 Second Affiliated Hospital of Chengdu Medical College, China National Nuclear Corporation 416 Hospital, 610051 Chengdu, Sichuan, China
4 West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, 610041 Chengdu, Sichuan, China
5 Institute of Preventive Medicine, Fourth Military Medical University, 710032 Xi’an, Shaanxi, China
6 NHC Key Laboratory of Nuclear Technology Medical Transformation (Mianyang Central Hospital), 621099 Mianyang, Sichuan, China
*Correspondence: (Jie Zhang); (Shuyu Zhang)
These authors contributed equally.
Academic Editor: Raffaele Capasso
Front. Biosci. (Landmark Ed) 2022, 27(7), 214;
Submitted: 28 March 2022 | Revised: 6 June 2022 | Accepted: 28 June 2022 | Published: 7 July 2022
(This article belongs to the Special Issue The Role of PPAR Receptors in Human Health)
Copyright: © 2022 The Author(s). Published by IMR Press.
This is an open access article under the CC BY 4.0 license.

Background: Radiation facilities and radioactive materials have been widely used in military, industry, medicine, science and nuclear facilities, which has significantly increased the potential of large-scale, uncontrolled exposure to radiation. The skin is one of the radiosensitive organ systems and radiation-induced skin injury remains a serious concern after ionizing radiation exposure. Our previous report indicates the involvement of the peroxisome proliferator-activated receptor pathway in the response of skin tissues to ionizing radiation. PPARα is a member of the PPAR nuclear hormone receptor superfamily, which can be activated by fibrate ligands. However, the protection of fenofibrate against ionizing radiation in skin keratinocytes and fibroblasts has not been described. Methods: The PPARα mRNA levels in irradiated and nonirradiated skin tissues of rats were determined by real-time assay. The expression of PPARα, and FABP4 were evaluated by western blot and IHC assay. The cell proliferation was detected by colony formation. The γH2AX foci and ROS levels in irradiated WS1 cells with FABP4 overexpression than in control cells were performed by Immunofluorescence assay. Results: We found that PPARα expression was lower in the irradiated skin tissues of mouse, rat, monkey, and human patients than in their nonirradiated counterparts. PPARα fenofibrate significantly decreased radiation-induced ROS and apoptosis in a dose-dependent manner in human keratinocyte HaCaT and skin fibroblast WS1 cells. Moreover, fenofibrate significantly decreased radiation-induced ROS and malondialdehyde (MDA) levels in electron beam irradiated skin tissues of rats. Mechanistically, the proximal promoter of fatty acid binding protein 4 (FABP4) harbored three binding sites of PPARα and fenofibrate stimulated the transcription of FABP4 in skin cells. FABP4 overexpression decreased radiation-induced ROS and γH2AX foci. FABP4 inhibitor BMS309403 abrogated the ROS-eliminating activity as well as the lipid-accumulating role of fenofibrate, indicating that FABP4 mediates the radioprotective role of fenofibrate. In addition, FABP4 overexpression significantly decreased radiation-induced oxidative damage in vivo. Conclusions: These results confirm that fenofibrate attenuated radiation-induced oxidative damage to the skin by stimulating FABP4.

ionizing radiation
radiation-induced skin injury
peroxisome proliferator-activated receptor α (PPARα)
fatty acid binding protein 4 (FABP4)
82073477/National Natural Science Foundation of China
31770909/National Natural Science Foundation of China
81773226/National Natural Science Foundation of China
32071238/National Natural Science Foundation of China
2021-YF05-01603-SN/Military Logistics Research Program, Innovation Project of Chengdu
2021ZYD0073/Young Talent Project of China National Nuclear Corporation and Central Government Funds of Guiding Local Scientific and Technological Development for Sichuan Province
Fig. 1.
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