Dysregulation of LXR responsive genes contribute to ichthyosis in trichothiodystrophy.
ATP Binding Cassette Transporter, Subfamily G, Member 1
/ genetics
ATP-Binding Cassette Transporters
/ genetics
Animals
Cells, Cultured
Cholesterol
/ metabolism
Disease Models, Animal
Fibroblasts
/ metabolism
Gene Expression Regulation
Humans
Ichthyosis
/ genetics
Keratinocytes
/ metabolism
Liver X Receptors
/ metabolism
Mice
Primary Cell Culture
Skin
/ cytology
Transcription, Genetic
Trichothiodystrophy Syndromes
/ complications
Ichthyosis
LXR
Trichothiodystrophy
Journal
Journal of dermatological science
ISSN: 1873-569X
Titre abrégé: J Dermatol Sci
Pays: Netherlands
ID NLM: 9011485
Informations de publication
Date de publication:
Mar 2020
Mar 2020
Historique:
received:
15
10
2019
revised:
29
12
2019
accepted:
21
01
2020
pubmed:
11
2
2020
medline:
26
1
2021
entrez:
11
2
2020
Statut:
ppublish
Résumé
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. The aim of this study was to understand the pathophysiological mechanism of ichthyosis in TTD, focused on the transcriptional dysregulation. 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. 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. 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.
Sections du résumé
BACKGROUND
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
OBJECTIVE
The aim of this study was to understand the pathophysiological mechanism of ichthyosis in TTD, focused on the transcriptional dysregulation.
METHODS
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
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
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.
Identifiants
pubmed: 32037099
pii: S0923-1811(20)30042-6
doi: 10.1016/j.jdermsci.2020.01.012
pii:
doi:
Substances chimiques
ABCG1 protein, mouse
0
ATP Binding Cassette Transporter, Subfamily G, Member 1
0
ATP-Binding Cassette Transporters
0
Abca12 protein, mouse
0
Liver X Receptors
0
Cholesterol
97C5T2UQ7J
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
201-207Informations de copyright
Copyright © 2020 Japanese Society for Investigative Dermatology. Published by Elsevier B.V. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of Competing Interest The authors have no conflict of the interest to declare.