Differentiation disturbance in keratinocytes lacking the epidermal fatty acid binding protein gene (E-FABP) which is overexpressed in psoriatic lesions.

脂肪酸结合蛋白(FABP)被认为是脂类穿梭，溶解疏水性脂肪酸并将它们运送到适当的胞质内位置。在至少由13种异构体组成的FABP中，角质形成细胞只表达表皮型FABP(E-FABP)，在银屑病和愈合创面等活跃的增殖状态下过度表达。我们利用E-FABP缺失的角质形成细胞分析了E-FABP的功能。我们的检查显示E-FABP缺失的表皮中脂肪酸的数量减少，尤其是亚油酸。尽管E-FABP缺失的角质形成细胞的生长与野生细胞无差异，但E-FABP缺失的角质形成细胞对分化特异性蛋白(角蛋白1和Inscrin)的诱导作用减弱。亚油酸不直接调节角质形成细胞的分化，但亚油酸的衍生物羟基十八碳二烯酸(HODE)诱导角质形成细胞分化的特异性蛋白。此外，HODE激活了NF-kB信号通路，促进了角质形成细胞的分化。在E-FABP缺失的角质形成细胞中，NF-kB通路活性降低，这支持亚油酸的减少通过亚油酸的衍生物与分化障碍有关。另一方面，已被报道为E-FABP主要靶点的PPAR通路在E-FABP缺失的角质形成细胞中没有显示出任何差异。从我们的结果来看，E-FABP通过脂肪酸代谢影响了核因子-kB途径，这可能与E-FABP的过度表达与银屑病的发病机制有关，因为核因子-kB在细胞的存活和分化中起着重要作用。

Fatty acid binding proteins (FABP) is postulated to serve as a lipid shuttle, solubilizing hydrophobic fatty acids and delivering them to the appropriate intracytoplasmic sites. Among FABP consisting of at least 13 isoforms, keratinocytes only express epidermal-type FABP (E-FABP) which is overexpressed in actively proliferating states like psoriasis and healing wounds. We analyzed functions of E-FABP using E-FABP null keratinocytes. Our examinations revealed decreased amount of fatty acids, especially of linoleic acid, in the E-FABP null epidermis. Although no difference in the growth of the E-FABP null keratinocytes with that of wild cells, the null keratinocytes showed decrease of induction of differentiation specific proteins (keratin 1 and involcrin). Linoleic acid did not modulate the keratinocyte differentiation directly, but linoleic acid derivatives, hydroxyoctadecadienoic acid (HODE), induced the differentiation specific proteins. Moreover, HODE activated NF-kB signal pathway which promoted keratinocyte differentiation. The activity of NF-kB pathway was decreased in the E-FABP null keratinocytes, which supported the idea that the decreased linoleic acid connects disturbed differentiation via the derivatives of linoleic acid. On the other hand, peroxisome proliferator activated receptor (PPAR) pathway, which had been reported as main target of E-FABP, did not show any difference in the E-FABP null keratinocytes. From our results, E-FABP affects NF-kB pathway through fatty acid metabolism, which may connect E-FABP overexpression with pathomechanism in psoriasis because NF-kB plays important roles in cell survival and differentiation.