Fenofibrate Attenuates Radiation-Induced Oxidative Damage to the Skin through Fatty Acid Binding Protein 4 (FABP4)

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: zhangjie78@fmmu.edu.cn (Jie Zhang); zhang.shuyu@hotmail.com (Shuyu Zhang)
^†These authors contributed equally.
Academic Editor: Raffaele Capasso

Front. Biosci. (Landmark Ed) 2022, 27(7), 214; https://doi.org/10.31083/j.fbl2707214

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)

This is an open access article under the CC BY 4.0 license.

Abstract

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. PPAR $\alpha{}$ 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 PPAR $\alpha{}$ mRNA levels in irradiated and nonirradiated skin tissues of rats were determined by real-time assay. The expression of PPAR $\alpha{}$ , and FABP4 were evaluated by western blot and IHC assay. The cell proliferation was detected by colony formation. The $\gamma{}$ H2AX foci and ROS levels in irradiated WS1 cells with FABP4 overexpression than in control cells were performed by Immunofluorescence assay. Results: We found that PPAR $\alpha{}$ expression was lower in the irradiated skin tissues of mouse, rat, monkey, and human patients than in their nonirradiated counterparts. PPAR $\alpha{}$ 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 PPAR $\alpha{}$ and fenofibrate stimulated the transcription of FABP4 in skin cells. FABP4 overexpression decreased radiation-induced ROS and $\gamma{}$ H2AX 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.

Keywords

ionizing radiation

radiation-induced skin injury

peroxisome proliferator-activated receptor α (PPARα)

fenofibrate

fatty acid binding protein 4 (FABP4)

Funding

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

Figures

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Fig. 1.

Ionizing radiation decreases the expression of PPAR $\alpha{}$ expression in skin tissues. (A) PPAR $\alpha{}$ mRNA levels in irradiated and nonirradiated skin tissues of rats (n = 5). PPAR $\alpha{}$ mRNA expression was measured by real-time PCR. The data are shown as the mean $\pm$ SEM. (B) The expression of PPAR $\alpha{}$ in irradiated and nonirradiated skin tissues of mouse, rat and monkey. Skin tissues were collected three days after indicated radiation doses. PPAR $\alpha{}$ expression was measured by IHC as described in the Materials and Methods section. (C) The expression of PPAR $\alpha{}$ in nonirradiated and irradiated human skin tissues. (D) Western blotting analyses of PPAR $\alpha{}$ expression at different doses of radiation in WS1 and HaCaT cells. (E) Quantitative analysis of Western blotting assay. Data are depicted as the mean $\pm$ SD from three independent experiments. * p $<$ 0.05; ** p $<$ 0.01, compared with the control group.

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