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PPARδ agonists upregulate transcripts in the ω-O-acylceramide pathway essential for the formation of corneocyte lipid envelopes in epidermis and pathogenic in ichthyosis
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper. (Dermatology and Venerology)ORCID-id: 0000-0001-9280-9832
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper. (Dermatology and Venerology)
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper. (Dermatology and Venerology)
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper. (http://orcid.org/0000-0002-3617-8551)ORCID-id: 0000-0002-3617-8551
(Engelska)Manuskript (preprint) (Övrigt vetenskapligt)
Abstract [en]

At least twelve proteins are involved in the biosynthesis and transport of ω-O-acylceramide (acylCer), a lipid which is covalently attached to the cornified cell envelope of epidermal keratinocytes essential for a proper permeability barrier. Deleterious mutations in any of the involved genes may cause autosomal recessive congenital ichthyosis (ARCI). The regulation of mRNA transcripts involved in the acylCer pathway is sparsely studied although it is known that retinoids reduce the expression of most of these transcripts and that peroxisome proliferator-activated receptor-d (PPARd) agonists induce the expression of at least three genes (ABCA12, CERS3 and ELOVL4). In this study, we examined the effect of several PPAR agonists on the mRNA expression of twelve ARCI-related genes in cultured human epidermal keratinocytes. In short, PPARd agonists, but not PPARa- and PPARg-agonists, markedly induced the genes after 24 hours exposure, and the induction was more pronounced in pre-confluent proliferating cells as compared to post-confluent differentiated cells, although the latter cells showed a much higher baseline expression. For eight of the genes the induction by PPARd-agonist GW501516 could be abolished by pre-treatment with PPARd-antagonist GSK0660. Reassuringly, GW501516 induced the same genes also in human epidermal equivalents. These results suggest that ligand activation of PPARd should be tested for its ability to restore a defect skin barrier caused by an insufficient production of acylCer.

Nyckelord [en]
peroxisome proliferator-activated receptors, genodermatoses, transcription
Nationell ämneskategori
Dermatologi och venereologi
Forskningsämne
Dermatologi och venereologi
Identifikatorer
URN: urn:nbn:se:uu:diva-377553OAI: oai:DiVA.org:uu-377553DiVA, id: diva2:1290848
Forskningsfinansiär
Vetenskapsrådet, K2013-57X-22309-3Tillgänglig från: 2019-02-21 Skapad: 2019-02-21 Senast uppdaterad: 2019-02-21
Ingår i avhandling
1. Congenital Recessive Ichthyosis: Studies of Gene Expressions Related to Keratinocyte Differentiation and Skin Barrier Repair
Öppna denna publikation i ny flik eller fönster >>Congenital Recessive Ichthyosis: Studies of Gene Expressions Related to Keratinocyte Differentiation and Skin Barrier Repair
2019 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
Abstract [en]

Autosomal recessive congenital ichthyosis (ARCI) is a rare monogenetic disorder characterized by a defective skin barrier, hyperkeratosis, and dry, scaly skin. It affects keratinocyte differentiation and is caused by mutations in any of at least 12 genes believed to control the formation of ω-O-acylceramide and the corneocyte lipid envelope (CLE): ABCA12, ALOXE3, ALOX12B, CERS3, CYP4F22, ELOVL4, LIPN, NIPAL4, PNPLA1, SDR9C7, SLC27A4, and TGM1.

Studies of keratinocyte differentiation and gene expression in ARCI may help us better understand the pathobiology of skin barrier formation. One way to verify that ARCI-related gene products are operating in a chain of events essential for lipid barrier formation is to use immunofluorescence and in situ proximity ligation assays to demonstrate the proteins’ colocalizations in the epidermis. In paper I, a new method for the objective quantitative image analysis of protein expression and colocalization in different epidermal layers of skin sections was developed using free, open-source software, CellProfiler. Using this method and microarray analyses of skin biopsies from ARCI patients with TGM1 mutations (n = 5) compared with those of healthy controls (n = 4), many ARCI-related genes were found to be upregulated in patient epidermis (paper II). Because many other genes involved in keratinocyte differentiation and immune/inflammatory response, including PPARD, were also induced in the patients’ microarrays, the effects of a ligand-dependent transcription factor, PPARδ, encoded by PPARD, were studied on ARCI-related gene expression in cultured keratinocytes, usually showing the pronounced upregulation by PPARδ agonists (paper III). Furthermore, using previous array data obtained from cultured differentiated keratinocytes and from skin biopsies of patients with TGM1 mutations, nine novel candidate markers of differentiation were identified, and the upregulation was verified by qPCR of mRNA from cultured keratinocytes and skin biopsies. These transcripts were also induced by PPARδ agonists in cultured proliferating keratinocytes (paper IV).

To conclude, the upregulation of other ARCI-related genes in patients with TGM1 mutations might reflect a feedback mechanism in ω-O-acylceramide biosynthesis, which, however, is unable to restore the patients’ skin barrier. In theory, substitution therapy with ω-O-acylceramide and recombinant TGm-1 may be required. Because PPARδ activation appears involved in upregulating ARCI-related genes and nine novel differentiation marker genes, all potentially important for barrier repair, this approach could become a treatment option for several types of ichthyosis and wound healing.

Ort, förlag, år, upplaga, sidor
Uppsala: Acta Universitatis Upsaliensis, 2019. s. 58
Serie
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1541
Nyckelord
genodermatoses, oligoarray, trancriptomics, transglutaminase-1, cornified envelope, peroxisome proliferator-activated receptor δ, all-trans retinoic acids.
Nationell ämneskategori
Dermatologi och venereologi
Forskningsämne
Dermatologi och venereologi
Identifikatorer
urn:nbn:se:uu:diva-377557 (URN)978-91-513-0578-3 (ISBN)
Disputation
2019-04-11, Fåhraeussalen, Rudbeck Laboratory, C5, entréplan, Uppsala, 13:15 (Engelska)
Opponent
Handledare
Tillgänglig från: 2019-03-20 Skapad: 2019-02-21 Senast uppdaterad: 2019-05-07

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Zhang, HanqianTörmä, Hans
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Dermatologi och venereologi

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