Sun Chuntang, Song Bin, Sheng Wenjiong, Yu Daojiang, Yang Tingyi, Geng Fenghao, Fang Kai, Jiao Yang, Zhang Jie, Zhang Shuyu
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.
State Key Lab of Radiation Medicine and Protection, School of Radiation Medicine and Protection, Medical College of Soochow University, 215123 Suzhou, Jiangsu, China.
Front Biosci (Landmark Ed). 2022 Jul 7;27(7):214. doi: 10.31083/j.fbl2707214.
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.
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.
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 .
These results confirm that fenofibrate attenuated radiation-induced oxidative damage to the skin by stimulating FABP4.
辐射设施和放射性物质已广泛应用于军事、工业、医学、科学和核设施中，这显著增加了大规模、无控制辐射暴露的可能性。皮肤是对辐射敏感的器官系统之一，电离辐射暴露后，辐射诱导的皮肤损伤仍然是一个严重问题。我们之前的报告表明，过氧化物酶体增殖物激活受体途径参与皮肤组织对电离辐射的反应。PPARα是PPAR核激素受体超家族的成员，可被贝特类配体激活。然而，非诺贝特对皮肤角质形成细胞和成纤维细胞电离辐射的保护作用尚未见报道。
通过实时检测法测定大鼠受照射和未受照射皮肤组织中PPARα mRNA水平。通过蛋白质免疫印迹法和免疫组化法评估PPARα和FABP4的表达。通过集落形成检测细胞增殖。通过免疫荧光法检测FABP4过表达的受照射WS1细胞中的γH2AX焦点和ROS水平。
我们发现，在小鼠、大鼠、猴子和人类患者受照射的皮肤组织中，PPARα表达低于未受照射的对应组织。非诺贝特可使人类角质形成细胞HaCaT和皮肤成纤维细胞WS1中辐射诱导的ROS和凋亡呈剂量依赖性显著降低。此外，非诺贝特可使大鼠电子束照射皮肤组织中辐射诱导的ROS和丙二醛（MDA）水平显著降低。机制上，脂肪酸结合蛋白4（FABP4）的近端启动子含有三个PPARα结合位点，非诺贝特可刺激皮肤细胞中FABP4的转录。FABP4过表达可降低辐射诱导的ROS和γH2AX焦点。FABP4抑制剂BMS309403消除了非诺贝特的ROS消除活性以及脂质积累作用，表明FABP4介导非诺贝特的辐射防护作用。此外，FABP4过表达可显著降低辐射诱导的氧化损伤。
这些结果证实，非诺贝特通过刺激FABP4减轻辐射诱导的皮肤氧化损伤。
