Ligand-activation of the aryl hydrocarbon receptor up-regulates epidermal UDP-glucose ceramide glucosyltransferase and glucosylceramides

Ligand-activation of the Aryl Hydrocarbon Receptor (AHR) accelerates keratinocyte differentiation and the formation of the epidermal permeability barrier (EPB). Several classes of lipids, including ceramides, are critical to the EPB. In normal human epidermal keratinocytes, the AHR ligand, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), increased RNA levels of ceramide metabolism and transport genes, UDP-glucose ceramide glucotransferase (UGCG), ATP binding cassette subfamily A member 12 (ABCA12), glucosylceramidase beta (GBA1) and sphingomyelin phosphodiesterase 1 (SMPD1). Levels of abundant skin ceramides were also increased by TCDD. These included the metabolites synthesized by UGCG, glucosylceramides and acyl glucosylceramides. Chromatin immunoprecipitation-sequence analysis and luciferase reporter assays identified UGCG as a direct AHR target. The AHR antagonist, GNF351, inhibited the TCDD-mediated RNA and transcriptional increases. Tapinarof, an AHR ligand approved for the treatment of psoriasis, increased UGCG RNA, protein and its lipid metabolites hexosylceramides, as well as increased the expression of ABCA12, GBA1 and SMPD1. In Ahr-null mice, Ugcg RNA and hexosylceramides were lower compared to wild-type. These results indicate that the AHR regulates the expression of UGCG, a ceramide metabolizing Enzyme required for ceramide trafficking, keratinocyte differentiation, and EPB formation.