Differentiation of epidermal keratinocytes is dependent on glucosylceramide:ceramide processing.

Abstract

Skin barrier function is primarily assigned to the outer epidermal layer, the stratum corneum (SC), mainly composed of corneocytes and lipid-enriched extracellular matrix. Epidermal ceramides (Cers) are essential barrier lipids, containing ultra-long-chain (ULC) fatty acids (FAs) with a unique ω-hydroxy group, which is necessary for binding to corneocyte proteins. In the SC, Cers are believed to derive from glucosylated intermediates, namely glucosylceramides (GlcCers), as surmised from human Gaucher's disease and related mouse models. Tamoxifen (TAM)-induced deletion of the endogenous GlcCer-synthesizing enzyme UDP-glucose:ceramide glucosyltransferase (UGCG) in keratin K14-positive cells resulted in epidermal GlcCer depletion. Although free extractable Cers were elevated in total epidermis and as well in SC, protein-bound Cers decreased significantly in Ugcg(f/fK14CreERT2) mice, indicating glucosylation to be required for regular Cer processing as well as arrangement and extrusion of lipid lamellae. The almost complete loss of protein-bound Cers led to a disruption of the water permeability barrier (WPB). UGCG-deficient mice developed an ichthyosis-like skin phenotype marked by impaired keratinocyte differentiation associated with delayed wound healing. Gene expression profiling of Ugcg-mutant skin revealed a subset of differentially expressed genes involved in lipid signaling and epidermal differentiation/proliferation, correlating to human skin diseases such as psoriasis and atopic dermatitis. Peroxisome proliferator-activated receptor beta/delta (PPARβ/δ), a Cer-sensitive transcription factor was identified as potential mediator of the altered gene sets.

• Authors: Nicole Amen, Daniel Mathow, Mariona Rabionet, Roger Sandhoff, Lutz Langbein, Norbert Gretz, Carsten Jäckel, Hermann-Josef Gröne, Richard Jennemann
• Journal: Human molecular genetics (Hum Mol Genet) Vol. 22 Issue 20 Pg. 4164-79 (Oct 15 2013) ISSN: 1460-2083 [Electronic] England
• PMID: 23748427 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Ceramides
• Glucosylceramides
• Lipids
• Peroxisome Proliferator-Activated Receptors
• Glucosyltransferases
• ceramide glucosyltransferase

Topics

• Animals
• Cell Differentiation
• Ceramides (metabolism)
• Epidermal Cells
• Epidermis (metabolism)
• Gene Expression Profiling
• Glucosylceramides (metabolism)
• Glucosyltransferases (genetics, metabolism)
• Humans
• Keratinocytes (cytology, metabolism)
• Lipids (biosynthesis)
• Mice
• Peroxisome Proliferator-Activated Receptors (genetics, metabolism)
• Phenotype
• Signal Transduction (genetics)
• Skin Physiological Phenomena