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Interactions between FATP4 and ichthyin in epidermal lipid processing may provide clues to the pathogenesis of autosomal recessive congenital ichthyosis
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Dermatology and Venereology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Dermatology and Venereology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Dermatology and Venereology.
2013 (English)In: Journal of dermatological science (Amsterdam), ISSN 0923-1811, E-ISSN 1873-569X, Vol. 69, no 3, 195-201 p.Article in journal (Refereed) Published
Abstract [en]

Background:

Autosomal recessive congenital ichthyosis (ARCI) is caused by mutations in 10 differentgenes, of which transglutaminase-1 (TGM1) predominates. A rare form is ichthyosis prematuritysyndrome (IPS) caused by mutations in SLC27A4 encoding fatty acid transporter protein 4 (FATP4),believed to be an acyl-CoA synthetase activating long- and very-long-chain FA. Another ARCI is caused bymutations in NIPAL4, coding for ichthyin, which is proposed to be a magnesium transporter or a transmembrane receptor. A possible interaction between FATP4 and ichthyin has not been studied before.

Objective:

To find common denominators in the pathogenesis of ARCI.

Methods:

FATP4 and ichthyin were analyzed by immunofluorescence and proximity ligation assay (PLA) in healthy and ARCI patient skin and in in vitro models of ARCI epidermis.

Results:

Both proteins were expressed in the upper stratum granulosum of normal epidermis and PLA confirmed a close interaction between FATP4 and ichthyin. In IPS skin lacking FATP4 we found reduced ichthyin expression and this finding could be reproduced in organotypic epidermis with siRNA silenced SLC27A4. In contrast, increased FATP4 staining was found in patients with ichthyin (NIPAL4) mutations and in organotypic epidermis with silenced NIPAL4. In patients with TGM1 mutations, the expression of both FATP4 and ichthyin was increased, but the PLA signal was low probably indicating a malfunctioning protein interaction.

Conclusion:

Our study suggests that FATP4, ichthyin and TGM1 interact in lipid processing essential for maintaining the epidermal barrier function. It is also hypothesized that ichthyin serves as Mg2+-transporter for FATP4 in this process.

Place, publisher, year, edition, pages
2013. Vol. 69, no 3, 195-201 p.
National Category
Dermatology and Venereal Diseases
Research subject
Medical Science
Identifiers
URN: urn:nbn:se:uu:diva-172440DOI: 10.1016/j.jdermsci.2012.11.593ISI: 000316714800004OAI: oai:DiVA.org:uu-172440DiVA: diva2:514678
Available from: 2012-04-10 Created: 2012-04-10 Last updated: 2017-12-07Bibliographically approved
In thesis
1. In vitro Studies of Genodermatoses Affecting Cytoskeletal Integrity and Lipid Processing in Human Epidermis: Pathogenic Mechanisms and Effects of Retinoid Therapy
Open this publication in new window or tab >>In vitro Studies of Genodermatoses Affecting Cytoskeletal Integrity and Lipid Processing in Human Epidermis: Pathogenic Mechanisms and Effects of Retinoid Therapy
2012 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Autosomal dominant epidermolytic ichthyosis (EI) is a rare disease characterized by intra-epidermal blistering due to mutations in either of two keratin genes, KRT1 and KRT10, expressed by suprabasal keratinocytes. Autosomal recessive congenital ichthyosis (ARCI) is a non-blistering, hyperkeratotic disease caused by mutations in one of the following genes: ABCA12, ALOX12B, ALOXE3, TGM1, CYP4F22, NIPAL4 and SLC27A4, which are all essential for skin barrier homeostasis. ARCI and EI often respond well to treatment with retinoids, but the mechanism of action is unclear. The aim of this thesis was to increase the knowledge of pathogenic pathways in ichthyosis and to find new explanations to the effect of retinoids.

In vitro studies of immortalized keratinocytes from EI patients showed an abnormal keratin aggregation after heat stress, that could be partially inhibited by pre-treatment with all-trans retinoic acid (ATRA) or retinoic acid receptor α-agonists. ATRA treatment also reduced the relative expression of mutated vs wildtype KRT10. The clearance of ATRA in human keratinocytes was found to be mediated by CYP26B1.

In skin biopsies from ARCI patients, immunofluorescence analysis of 12R-LOX, eLOX-3, TGM1, ichthyin and FATP4 showed altered expression, not only of the mutated protein, but also of the other proteins. These observations are consistent with a feedback regulatory mechanism by which the loss of one protein results in an up-regulation of other proteins. Furthermore, 12R-LOX, eLOX-3 and TGM1 were intimately co-localized in stratum corneum, as were ichthyin and FATP4, suggesting that the proteins are linked to the same metabolic pathway. When treated with a CYP26 inhibitor known to raise the endogenous ATRA level of the skin, two patients with NIPAL4 mutations, initially exhibiting increased co-localization signals for 12R-LOX and eLOX-3, displayed normalized lipoxygenase expressions and showed clinical improvement.

In conclusion, mechanisms are proposed by which pathogenic keratin aggregations in EI and epidermal protein deficiencies in ARCI patients may be mitigated by retinoids. Furthermore, the vivid crosstalk between proteins incriminated in ARCI suggests that these enzymes operate along a common metabolic pathway essential for producing barrier lipids in stratum corneum. Any abrogation of this production may cause barrier failure, hence resulting in a compensatory hyperkeratosis characteristic of congenital ichthyosis.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2012. 43 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 769
Keyword
Congenital Ichthyosiform Erythroderma, Epidermolytic Hyperkeratosis, Ceramides, Keratins, Retinoids, Molecular Probe Techniques, Transglutaminases, Lipoxygenases, Fatty Acid Transporter Proteins, Keratinocytes, Epidermis
National Category
Dermatology and Venereal Diseases
Research subject
Medical Science
Identifiers
urn:nbn:se:uu:diva-172863 (URN)978-91-554-8352-4 (ISBN)
Public defence
2012-06-04, Rosensalen, Akademiska sjukhuset entrance 95/96, Uppsala, 13:00 (Swedish)
Opponent
Supervisors
Available from: 2012-05-14 Created: 2012-04-16 Last updated: 2012-08-01Bibliographically approved

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Li, HaoVahlquist, AndersTörmä, Hans

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