PPAR and LXR activators regulate ABCA12 expression in human keratinocytes
PPAR and LXR activators regulate ABCA12 expression in human keratinocytes
复制标题
DOI：
10.1038/sj.jid.5700944
复制
发表时间：
2008-01-01
影响因子：
6.5
通讯作者：
Feingold, Kenneth R.
中科院分区：
文献类型：
--
作者：
Jiang, Yan J.;Lu, Biao;Feingold, Kenneth R.
ATP结合盒（ABC）转运蛋白家族12（ABCA 12）是ABC超家族的成员，其促进脂质递送至角质形成细胞中的板层体（LB），这对于渗透屏障功能至关重要。最近，ABCA 12基因突变被发现是导致丑角鱼鳞病和板层状鱼鳞病这两种破坏性皮肤疾病的基础。以前，我们和其他人已经证明，过氧化物酶体增殖物激活受体（PPARs）和肝脏X受体（LXR）的激活，通过刺激角质形成细胞分化，脂质合成，并增加LB的形成/分泌，改善表皮通透性屏障的稳态。在这里，我们报告，这两个PPAR-gamma和-β/δ激活剂显着刺激ABCA 12 mRNA的表达在培养的人角质形成细胞（CHK）的剂量和时间依赖性的方式。ABCA 12 mRNA水平的增加伴随着ABCA 12蛋白的增加，表明这种上调的生物学重要性。LXR激活剂也增加CHK中ABCA 12 mRNA水平，但程度较低。相反，PPAR-alpha、RAR、RXR或维生素D受体的激活剂不改变ABCA 12的表达。两个主要的ABCA 12替代转录物和它们相应的蛋白质也在未分化和分化的CHK中表达并被PPAR或LXR激活剂上调。总之，我们的数据表明，PPAR和LXR激活剂增加ABCA 12的表达，提供了一个额外的机制，通过该机制，PPAR和LXR激活剂促进表皮渗透屏障稳态。
ATP-binding cassette (ABC) transporter, family 12 (ABCA12), a member of the ABC superfamily, facilitates the delivery of lipids to lamellar bodies (LB) in keratinocytes, which is critical for permeability barrier function. Recently, gene mutations of ABCA12 were found to underlie Harlequin ichthyosis and lamellar ichthyosis, two devastating skin disorders. Previously we and others have demonstrated that peroxisome proliferators-activated receptors (PPARs) and liver X receptor (LXR) activation improved epidermal permeability barrier homeostasis by stimulating keratinocyte differentiation, lipid synthesis, and increasing LB formation/secretion. Here we report that both PPAR-gamma and -beta/delta activators markedly stimulate ABCA12 mRNA expression in cultured human keratinocyte (CHK) in a dose- and time-dependent manner. Increased ABCA12 mRNA levels are accompanied by an increase in ABCA12 protein, suggesting biological importance of this upregulation. LXR activators also increase ABCA12 mRNA levels in CHK, but to a lesser extent. In contrast, activators of PPAR-alpha, RAR, RXR, or vitamin D receptor did not alter ABCA12 expression. Two major ABCA12 alternative transcripts and their corresponding proteins are also expressed and upregulated by PPAR or LXR activator in both undifferentiated and differentiated CHK. Together, our data demonstrate that PPAR and LXR activators increase ABCA12 expression, providing an additional mechanism by which PPAR and LXR activators promote epidermal permeability barrier homeostasis.