Dysregulation of LXR responsive genes contribute to ichthyosis in trichothiodystrophy
Dysregulation of LXR responsive genes contribute to ichthyosis in trichothiodystrophy
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DOI：
10.1016/j.jdermsci.2020.01.012
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发表时间：
2020-03-01
影响因子：
4.6
通讯作者：
Egly, Jean-Marc
中科院分区：
文献类型：
--
作者：
Hashimoto, Satoru;Takanari, Hiroki;Egly, Jean-Marc
背景资料：毛发硫营养不良（TTD）是一种罕见的常染色体隐性遗传疾病，其特征是毛发易碎和各种全身症状，包括光敏性和鱼鳞病。虽然光敏性可能会导致DNA修复缺陷，其他TTD的临床特征可能是由于某些分子processes.Objectives的缺陷：本研究的目的是了解鱼鳞病在TTD的病理生理机制，集中在转录失调。方法：TTD小鼠皮肤组织和角质形成细胞的病理和生理检查，以确定脂质稳态的改变在TTD鱼鳞病。TTD患者和TTD小鼠角质形成细胞来源的成纤维细胞中的某些脂质转运蛋白的基因表达进行了评估。除了异常的胆固醇动力学，TTD小鼠角质形成细胞表现出受损的肝X受体（LXR）反应基因的表达，包括Abca12，一个关键的调节丑角鱼鳞病，和Abcg1是参与表皮中的胆固醇转运过程。引人注目的是，LXR反应基因的失调已被观察到的TTD患者谁开发ichthyosis.Conclusions：我们的研究结果表明，LXR反应基因的表达改变有助于TTD鱼鳞病的病理生理。这些发现为TTD提供了新的药物发现靶点。(C)2020日本皮肤病研究学会。Elsevier B.V.出版，保留所有权利。
Background: Trichothiodystrophy (TTD) is a rare autosomal recessive disorder characterised by brittle hairs and various systemic symptoms, including photosensitivity and ichthyosis. While photosensitivity could result from DNA repair defects, other TTD clinical features might be due to deficiencies in certain molecular processes.Objectives: The aim of this study was to understand the pathophysiological mechanism of ichthyosis in TTD, focused on the transcriptional dysregulation.Methods: TTD mouse skin tissue and keratinocytes were pathologically and physiologically examined to identify the alteration of lipid homeostasis in TTD with ichtyosis. Gene expression of certain lipid transporter was assessed in fibroblasts derived from TTD patients and TTD mouse keratinocytes.Results: Histopathology and electron microscopy revealed abnormal lipid composition in TTD mice skin. In addition to abnormal cholesterol dynamics, TTD mouse keratinocytes exhibit impaired expression of Liver X receptor (LXR) responsive genes, including Abca12, a key regulator of Harlequin ichthyosis, and Abcg1 that is involved in the cholesterol transport process in the epidermis. Strikingly, dysregulation of LXR responsive genes has been only observed in cells isolated from TTD patients who developed ichthyosis.Conclusions: Our results suggest that the altered expression of the LXR-responsive genes contribute to the pathophysiology of ichthyosis in TTD. These findings provide a new drug discovery target for TTD. (C) 2020 Japanese Society for Investigative Dermatology. Published by Elsevier B.V. All rights reserved.