Aloxe3 Knockout Mice Reveal a Function of Epidermal Lipoxygenase-3 as Hepoxilin Synthase and Its Pivotal Role in Barrier Formation
Aloxe3 Knockout Mice Reveal a Function of Epidermal Lipoxygenase-3 as Hepoxilin Synthase and Its Pivotal Role in Barrier Formation
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DOI：
10.1038/jid.2012.250
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发表时间：
2013-01-01
影响因子：
6.5
通讯作者：
Schneider, Holm
中科院分区：
文献类型：
--
作者：
Krieg, Peter;Rosenberger, Sabine;Schneider, Holm
脂氧合酶（LOX）基因ALOX12B和ALOXE3的功能缺失突变是常染色体隐性遗传性鱼鳞病的第二大常见原因。编码的蛋白12R-LOX和表皮LOX-3 （eLOX-3）依次通过r -氢过氧化物将脂肪酸底物转化为特定的环氧醇衍生物，并被认为在表皮屏障形成过程中以相同的代谢途径运作。在这里，我们发现小鼠的eLOX-3缺乏导致早期产后死亡，与之前报道的12r - lox敲除小鼠相似但程度较轻的屏障缺陷和形态变化相关。皮肤脂质分析表明，在12R-LOX-和elox -3缺失小鼠中，屏障衰竭的严重程度与共价结合神经酰胺的缺失有关，证实了LOX途径与神经酰胺加工和角质细胞脂质包膜形成的功能联系。此外，对游离含氧脂肪酸代谢物的分析显示，在缺乏eLOX-3的表皮中，hepoxilin代谢物水平显著降低，这表明eLOX-3在哺乳动物皮肤中作为与12S-LOX通路相关的hepoxilin合成酶具有额外的功能。Journal of Investigative Dermatology (2013) 133, 172-180；doi: 10.1038 / jid.2012.250;2012年7月26日在线发布
Loss-of-function mutations in the lipoxygenase (LOX) genes ALOX12B and ALOXE3 are the second most common cause of autosomal recessive congenital ichthyosis. The encoded proteins, 12R-LOX and epidermal LOX-3 (eLOX-3), act in sequence to convert fatty acid substrates via R-hydroperoxides to specific epoxyalcohol derivatives and have been proposed to operate in the same metabolic pathway during epidermal barrier formation. Here, we show that eLOX-3 deficiency in mice results in early postnatal death, associated with similar but somewhat less severe barrier defects and morphological changes than reported earlier for the 12R-LOX-knockout mice. Skin lipid analysis demonstrated that the severity of barrier failure is related to the loss of covalently bound ceramides in both 12R-LOX- and eLOX-3-null mice, confirming a proposed functional linkage of the LOX pathway to ceramide processing and formation of the corneocyte lipid envelope. Furthermore, analysis of free oxygenated fatty acid metabolites revealed strongly reduced levels of hepoxilin metabolites in eLOX-3-deficient epidermis, indicating an additional function of eLOX-3 in mammalian skin as a hepoxilin synthase linked to the 12S-LOX pathway. Journal of Investigative Dermatology (2013) 133, 172-180; doi:10.1038/jid.2012.250; published online 26 July 2012