Stimulation of PPARα promotes epidermal keratinocyte differentiation in vivo
Stimulation of PPARα promotes epidermal keratinocyte differentiation in vivo
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DOI：
10.1046/j.1523-1747.2000.00073.x
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发表时间：
2000-09-01
影响因子：
6.5
通讯作者：
Feingold, KR
中科院分区：
文献类型：
--
作者：
Kömüves, LG;Hanley, K;Feingold, KR
我们近期的研究表明，过氧化物酶体增殖物激活受体α（PPARα）激动剂在培养的人角质形成细胞中刺激分化并抑制增殖，且在胎鼠皮肤外植体中加速表皮发育和通透屏障形成。由于PPARα激活在成年表皮中的作用尚不明确，本研究的目的是确定局部应用的PPARα配体是否调节小鼠表皮中的角质形成细胞分化。局部用PPARα激动剂处理导致表皮厚度降低。局部用PPARα激动剂处理后，棘层上部/颗粒层结构蛋白（兜甲蛋白、前丝聚蛋白 - 丝聚蛋白、兜甲下蛋白）的表达增加。此外，局部应用的PPARα激动剂还增加了细胞凋亡，减少了细胞增殖，并在急性屏障破坏后加速了屏障功能的恢复。对PPARα（-/-）基因敲除小鼠的实验表明，这些作用是通过PPARα特异性介导的。与PPARα（+/+）小鼠的表皮相比，PPARα（-/-）小鼠中兜甲蛋白、前丝聚蛋白 - 丝聚蛋白和兜甲下蛋白的表达略有降低。此外，局部用氯贝酸处理并未增加PPARα（-/-）小鼠的表皮分化。此外，在培养的人角质形成细胞中我们已经证明，PPARα激动剂诱导兜甲蛋白mRNA水平升高。我们还表明，这种基因表达的增加需要在 -2117至 -2111bp处有一个完整的激活蛋白 - 1（AP - 1）反应元件。因此，PPARα的激活刺激角质形成细胞/表皮分化并抑制增殖。
Our recent studies have demonstrated that PPAR alpha activators stimulate differentiation and inhibit proliferation in cultured human keratinocytes and accelerate epidermal development and permeability barrier formation in fetal rat skin explants. As the role of PPAR alpha activation in adult epidermis is not known, the aim of this study was to determine if topically applied PPAR alpha ligands regulate keratinocyte differentiation in murine epidermis. Topical treatment with PPAR alpha activators resulted in decreased epidermal thickness. Expression of structural proteins of the upper spinous/granular layers (involucrin, profilaggrin-filaggrin, loricrin) increased following topical treatment with PPAR alpha activators. Furthermore, topically applied PPAR alpha activators also increased apoptosis, decreased cell proliferation, and accelerated recovery of barrier function following acute barrier abrogation. Experiments with PPAR alpha(-/-) knockout mice showed that these effects are specifically mediated via PPAR alpha. Compared with the epidermis of PPAR alpha(+/+) mice, involucrin, profilaggrin-filaggrin, and loricrin expression were slightly decreased in PPAR alpha-/- mice. Moreover, topical clofibrate treatment did not increase epidermal differentiation in PPAR alpha-/- mice. Furthermore, in cultured human keratinocytes we have demonstrated that PPAR alpha activators induce an increase in involucrin mRNA levels. We have also shown that this increase in gene expression requires an intact AP-1 response element at -2117 to -2111 bp. Thus, stimulation of PPAR alpha stimulates keratinocyte/epidermal differentiation and inhibits proliferation.