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The expression of epidermal lipoxygenases and transglutaminase-1 is perturbed by NIPAL4 mutations: indications of a common metabolic pathway essential for skin barrier homeostasis
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.
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2012 (English)In: Journal of Investigative Dermatology, ISSN 0022-202X, E-ISSN 1523-1747, Vol. 132, no 10, 2368-2375 p.Article in journal (Refereed) Published
Abstract [en]

Autosomal recessive congenital ichthyosis (ARCI) is a heterogeneous group of skin barrier diseases due inter alia to mutations in transglutaminase-1 (TGM1), in lipoxygenases (LOXs) of the hepoxilin pathway, and in ichthyin, a putative Mg2+ transporter encoded by the NIPAL4 gene. In search of a common pathogenic pathway for ARCI, we investigated the epidermal expression of TGM1, 12R-LOX, eLOX-3, and ichthyin in skin biopsies from four healthy controls and nine patients with ARCI. In healthy skin, TGM1, ichthyin, and the LOX enzymes were predominantly expressed in the upper epidermis where colocalization signals could also be demonstrated by in situ proximity ligation assay. In patients with ALOX12B mutations and abnormal 12R-LOX expression, the colocalization signal for eLOX-3 and TGM1 was increased 4-fold. In contrast, patients with NIPAL4 mutations and abnormal ichthyin expression showed increased 12R-LOX and eLOX-3 staining and a colocalization signal of these LOXs that was three times the normal intensity. Treatment of these patients with a retinoid-mimetic drug, liarozole, normalized the expression of 12R-LOX and attenuated the colocalization signal. Altogether, our data indicate that ichthyin and TGM1 are functionally closely related in the lipid processing and that this metabolic pathway can be modified by retinoids.

Place, publisher, year, edition, pages
2012. Vol. 132, no 10, 2368-2375 p.
National Category
Dermatology and Venereal Diseases
Research subject
Medical Science; Dermatology and Venerology
Identifiers
URN: urn:nbn:se:uu:diva-172437DOI: 10.1038/jid.2012.160ISI: 000308909700011OAI: oai:DiVA.org:uu-172437DiVA: diva2:514677
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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