PNPLA1 has a crucial role in skin barrier function by directing acylceramide biosynthesis

Tetsuya Hirabayashi; Tatsuki Anjo; Arisa Kaneko; Yuuya Senoo; Akitaka Shibata; Hiroyuki Takama; Kohei Yokoyama; Yasumasa Nishito; Tomio Ono; Choji Taya; Kazuaki Muramatsu; Kiyoko Fukami; Agustí Mu?oz-Garcia; Alan R. Brash; Kazutaka Ikeda; Makoto Arita; Masashi Akiyama; Makoto Murakami

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PNPLA1 has a crucial role in skin barrier function by directing acylceramide biosynthesis

机译：PNPLA1通过指导酰基神经酰胺的生物合成在皮肤屏障功能中起关键作用

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Mutations in patatin-like phospholipase domain-containing 1 (PNPLA1) cause autosomal recessive congenital ichthyosis, but the mechanism involved remains unclear. Here we show that PNPLA1, an enzyme expressed in differentiated keratinocytes, plays a crucial role in the biosynthesis of ω- O -acylceramide, a lipid component essential for skin barrier. Global or keratinocyte-specific Pnpla1 -deficient neonates die due to epidermal permeability barrier defects with severe transepidermal water loss, decreased intercellular lipid lamellae in the stratum corneum , and aberrant keratinocyte differentiation. In Pnpla1 ?/? epidermis, unique linoleate-containing lipids including acylceramides, acylglucosylceramides and ( O -acyl)-ω-hydroxy fatty acids are almost absent with reciprocal increases in their putative precursors, indicating that PNPLA1 catalyses the ω- O -esterification with linoleic acid to form acylceramides. Moreover, acylceramide supplementation partially rescues the altered differentiation of Pnpla1 ?/? keratinocytes. Our findings provide valuable insight into the skin barrier formation and ichthyosis development, and may contribute to novel therapeutic strategies for treatment of epidermal barrier defects.

机译：含patatin样磷脂酶结构域1（PNPLA1）的突变引起常染色体隐性先天性鱼鳞病，但涉及的机制仍不清楚。在这里，我们显示PNPLA1，一种在分化的角质形成细胞中表达的酶，在ω-O-酰基神经酰胺（皮肤屏障所必需的脂质成分）的生物合成中起着关键作用。整体性或角质形成细胞特异性Pnpla1缺陷型新生儿死于表皮通透性屏障缺陷，伴有严重的表皮水分流失，角质层中的细胞间脂质薄层减少以及异常的角质形成细胞分化。在Pnpla1 ？/？表皮中，几乎不含独特的含亚油酸酯的脂质，包括酰基神经酰胺，酰基葡糖基神经酰胺和（O-酰基）-ω-羟基脂肪酸，其推定的前体几乎互不增加，表明PNPLA1催化与亚油酸的ω-O-酯化反应形成酰基神经酰胺。此外，补充酰基神经酰胺可部分挽救Pnpla1 的改变。角质形成细胞。我们的发现为皮肤屏障形成和鱼鳞病的发展提供了有价值的见解，并且可能有助于治疗表皮屏障缺陷的新型治疗策略。

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《Nature Communications》 |2017年第1期|共页
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Tetsuya Hirabayashi; Tatsuki Anjo; Arisa Kaneko; Yuuya Senoo; Akitaka Shibata; Hiroyuki Takama; Kohei Yokoyama; Yasumasa Nishito; Tomio Ono; Choji Taya; Kazuaki Muramatsu; Kiyoko Fukami; Agustí Mu?oz-Garcia; Alan R. Brash; Kazutaka Ikeda; Makoto Arita; Masashi Akiyama; Makoto Murakami;
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1. The role of PNPLA1 in omega-O-acylceramide synthesis and skin barrier function [J] . Hirabayashi Tetsuya, Murakami Makoto, Kihara Akio Biochimica et Biophysica Acta. Molecular and cell biology of Lipids . 2019,第6期

机译：pnpla1在ω-o-酰基合成和皮肤屏障功能中的作用
2. PNPLA1 is a transacylase essential for the generation of the skin barrier lipid ω-O-acylceramide [J] . Yusuke Ohno, Nozomi Kamiyama, Shota Nakamichi, Nature Communications . 2017,第1期

机译：PNPLA1是产生皮肤屏障脂质ω- O -酰基神经酰胺所必需的转酰基酶
3. Severe Skin Permeability Barrier Dysfunction in Knockout Mice Deficient in a Fatty Acid omega-Hydroxylase Crucial to Acylceramide Production [J] . Miyamoto Masatoshi, Itoh Narumi, Sawai Megumi, The Journal of investigative dermatology. . 2020,第2期

机译：严重的皮肤渗透性屏障功能障碍缺陷小鼠缺乏脂肪酸ω-羟化酶至丙基酰胺生产至关重要
4. Construction of Skin Impedance Model for Evaluation of Skin Barrier Functions in Case Wet-Type Electrode [C] . Y. Yamamoto, K. Shirai, T. Kusuhara International Conference on Biomedical Engineering . 2014

机译：湿型电极对皮肤屏障功能评估的皮肤阻抗模型的构建
5. I. Multicatalysis: Development of a Bismuth(III) triflate-catalyzed Nucleophilic addition/ Hydrofunctionalization Reaction in the Synthesis of Complex Heterocycles II. C--H Arylation of Arenes and Heteroarenes with Palladium-Carboxylate Catalysts: Identification of the Catalyst Resting State and the Crucial Role of Pivalate Ligand in Stabilization of the Catalyst III. C--H Arylation of Heteroarenes with Palladium-Carboxylate Catalysts: Importance of Phosphine Ligand for Basic Heteroarene Substrates IV. C--H Arylation of Heteroarenes with Palladium-Carboxylate Catalysts: Effect of the Properties of Basic Heteroarene Substrates on Direct Arylations. [D] . Tundel, Rachel E. 2011

机译：I.多催化作用：在复杂的杂环化合物的合成中三氟甲磺酸铋（III）催化的亲核加成/加氢官能化反应的发展。羰基钯催化剂对芳烃和杂芳烃的CH-H芳基化反应：催化剂静止状态的鉴定以及新戊酸酯配体在稳定催化剂中的关键作用III。羰基钯催化剂催化杂芳烃的CH芳基化：膦配体对基础杂芳烃基质的重要性IV。杂芳烃与钯-羧酸酯的CH芳基化：碱性杂芳烃底物性能对直接芳基化的影响。
6. PNPLA1 has a crucial role in skin barrier function by directing acylceramide biosynthesis [O] . Tetsuya Hirabayashi, Tatsuki Anjo, Arisa Kaneko, -1

机译：PNPLA1通过指导酰基神经酰胺的生物合成在皮肤屏障功能中起关键作用
7. Ceramides metabolism and impaired epidermal barrier in cutaneous diseases and skin aging: focus on the role of the enzyme PNPLA1 in the synthesis of ω-O-acylceramides and its pathophysiological involvement in some forms of congenital ichthyoses [O] . Nathalie Jonca 2019

机译：皮肤疾病和皮肤老化中的神经酰胺代谢和表皮屏障受损：重点关注酶PNPLA1在ω-O-酰基的合成中的作用及其在某些形式的先天性ICHTHYOSE中的病理生理学中的作用。

PNPLA1 has a crucial role in skin barrier function by directing acylceramide biosynthesis

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