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PPARα在UVB诱导皮肤损伤中的作用及潜在机制研究

Role and Potential Mechanisms of Peroxisome Proliferator-Activated Receptor α in Ultraviolet B Radiation-Induced Skin Damage

    摘要
  • 摘要:
    目的 太阳光中的中波紫外线（ultraviolet B, UVB）是WHO 1类致癌物，可以被表皮吸收，过量UVB照射会导致皮肤损伤和光老化。过氧化物酶体增殖物激活受体α（perixisome proliferator-activated receptor alpha, PPARα）是核受体家族的重要成员，在脂质代谢中发挥核心作用。本研究以PPARα－/－与野生型小鼠为对象，旨在观察并探讨PPARα缺失对UVB照射后损伤进程的影响及皮肤脂质谱的变化。
    方法 采用单次高剂量UVB照射（2 J/cm2）构建小鼠皮肤紫外光损伤模型，将C57BL/6J小鼠分为PPARα－/－组和野生型组，通过皮肤光损伤评分、苏木精-伊红（HE）染色、Western blot进行定性与定量分析。另采用连续多次低剂量UVB照射构建小鼠皮肤紫外光老化模型，将C57BL/6小鼠分为PPARα－/－组和野生型组，同样以HE染色和Western blot进行检测。此外，分别采集接受或不接受单次高剂量UVB照射（2 J/cm2）的两种基因型小鼠皮肤样本进行脂质组学分析。
    结果 在急性光损伤模型中，与野生型组小鼠相比，PPARα－/－组小鼠于照射后第0～32天内皮肤光损伤评分显著升高，伤口愈合速度更慢。在光老化模型中，与野生型组小鼠相比，PPARα－/－组小鼠皮肤细胞中衰老相关蛋白质表达水平上调（p16: 0.11±0.02 vs. 0.82±0.18, P<0.05； p21: 0.54±0.03 vs. 1.29±0.07, P<0.01；p53: 0.54±0.04 vs. 1.33±0.06, P<0.01；β-半乳糖苷酶: 0.80±0.06 vs. 1.20±0.15, P<0.05），同时皮肤毛囊数量减少、形态皱缩。脂质组学分析结果显示，UVB照射下PPARα缺失显著加剧了皮肤脂质代谢的紊乱，涉及神经酰胺（d18:1/30:2）、O-酰基-ω-羟基脂肪酸（44:4）、磷脂酰乙醇胺（50:1）、溶血磷脂酰胆碱（19:1）、溶血磷脂酰丝氨酸（44:11）和磷脂酰胆碱（19:1/20:1）等多种脂质的异常表达。
    结论 PPARα可以减轻UVB诱导的皮肤损伤和光老化，其缺失会加重皮肤损伤和脂质代谢紊乱。

     

    Abstract:
    Objective Ultraviolet B radiation (UVB) in sunlight is classified by the WHO as a Group 1 carcinogen. UVB is readily absorbed by the epidermis, and excessive exposure causes skin injury and photoaging. Peroxisome proliferator-activated receptor α (PPARα), a key member of the nuclear receptor family, plays a central role in lipid metabolism. This study aims to observe and investigate the effects of PPARα deletion on the progression of UVB-induced damage and changes in the skin lipid profile using PPARα-knockout (PPARα－/－) and wild-type mice.
    Methods A mouse model of ultraviolet-induced skin damage was established using excessive UVB exposure (2 J/cm²) administered for a single time. C57BL/6J mice were divided into PPARα－/－ and wild-type groups. Qualitative and quantitative analyses were performed using skin photodamage scoring, hematoxylin-eosin (HE) staining, and Western blotting. A photoaging model was established using repeated low-dose UVB exposure, and the C57BL/6 mice were again divided into PPARα－/－ and wild-type groups for qualitative and quantitative analyses through HE staining and Western blotting. Skin samples collected from PPARα－/－ and wild-type mice either sham-irradiated or exposed to a single dose 2 J/cm2 UVB irradiation were subjected to lipidomic analysis.
    Results In the photodamage model, PPARα－/－ mice exhibited significantly higher skin photodamage scores and delayed wound healing than wild-type controls on days 0-32 after a single excessive UVB exposure. In the photoaging model, the expression levels of senescence-associated proteins were markedly up-regulated in the skin of PPARα－/－ mice compared with wide-type mice (wild-type vs. PPARα－/－) (p16: 0.11 ± 0.02 vs. 0.82 ± 0.18, P < 0.05; p21: 0.54 ± 0.03 vs. 1.29 ± 0.07, P < 0.01; p53: 0.54 ± 0.04 vs. 1.33 ± 0.06, P < 0.01; β-galactosidase: 0.80 ± 0.06 vs. 1.20 ± 0.15, P < 0.05). In addition, PPARα－/－ mice exhibited reduced numbers of hair follicles and follicular atrophy. Lipidomic analysis revealed that PPARα deletion aggravated UVB-induced skin lipid metabolic disturbances, involving aberrant expression of multiple lipids, including Cer(d18:1/30:2), OAHFA(44:4), PE(50:1), LPC(19:1), LPS(44:11), and PC(19:1/20:1).
    Conclusion PPARα plays a protective role in UVB-induced skin damage and photoaging. Its deficiency aggravates skin damage and lipid metabolic disturbances.

     

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