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）被认为是脂质穿梭者，可溶解疏水脂肪酸并将其运送到适当的胞浆内部位。在由至少13种亚型组成的FABP中，角质形成细胞仅表达表皮型FABP (E-FABP)，在银屑病和伤口愈合等活跃增殖状态下过度表达。我们使用E-FABP空角质形成细胞分析E-FABP的功能。我们的检查显示E-FABP缺失表皮中脂肪酸，尤其是亚油酸的含量减少。虽然E-FABP空角质形成细胞的生长与野生细胞没有差异，但空角质形成细胞诱导分化特异性蛋白（角蛋白1和involcrin）的能力下降。亚油酸不直接调节角质细胞的分化，但亚油酸衍生物羟基十八烯二烯酸（HODE）可诱导分化特异性蛋白。此外，HODE激活NF-kB信号通路，促进角质细胞分化。在E-FABP缺失的角质形成细胞中，NF-kB通路的活性降低，这支持了亚油酸减少通过亚油酸衍生物连接干扰分化的观点。另一方面，作为E-FABP主要靶点的过氧化物酶体增殖物激活受体（PPAR）通路在E-FABP无角化细胞中没有表现出任何差异。从我们的研究结果来看，E-FABP通过脂肪酸代谢影响NF-kB通路，这可能将E-FABP过表达与银屑病的病理机制联系起来，因为NF-kB在细胞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.