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Orally Administered Glucosylceramide Improves the Skin Barrier Function by Upregulating Genes Associated with the Tight Junction and Cornified Envelope Formation

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Orally Administered Glucosylceramide Improves the Skin Barrier Function by Upregulating Genes Associated with the Tight Junction and Cornified Envelope Formation 110215 (251) Biosci. Biotechnol. Biochem., 75 (8), 110215-1–8, 2011 Orally Administered Glucosylceramide Improves the Skin Barrier Function by Upregulating Genes Associated with the Tight Junction and Cornified Envelope Formation y Ritsuro IDETA, Tomohiro SAKUTA, Yusuke NAKANO, and Taro UCHIYAMA Shiseido Functional Food Research and Development Center, 2-12-1 Fukuura, Kanazawa-ku, Yokohama 236-8643, Japan Received March 18, 2011; Accepted May 9, 2011; Online Publication, August 7, 2011 [doi:10.1271/bbb.110215] Dietary glucosylceramide improves the skin barrier mammalian skin barrier function through their role as function. We used a microarray system to analyze the intracellular lipids.6) The skin barrier is essential for mRNA expression in SDS-treated dorsal skin of the protecting against physical stimuli, thermal challenge, hairless mouse to elucidate the molecular mechanisms ultraviolet light (UV), chemical substances and micro- involved. The transepidermal water loss of mouse skin organisms, as well as for preventing water loss.7) The was increased by the SDS treatment, this increase being barrier function is mainly localized in the stratum significantly reduced by a prior oral administration of corneum (SC) which is formed in the outermost layer of glucosylceramides. The microarray-evaluated mRNA the epidermis and consists of the cornified envelope expressionAdvance ratio showed a statistically significant View in- (CE) and intercellular multilamellar lipids. CE forms crease in the expression of genes related to the cornified a highly durable and flexible barrier8) comprising a envelope and tight junction formation when compared 15-nm-thick structure composed of such insoluble with all genes in the glucosylceramide-fed/SDS-treated proteins as involucrin, loricrin, and small proline-rich mouse skin. We then examined the contribution of proteins that are covalently cross-linked by transgluta- glucosylceramide metabolites to the tight junction minases (TGases).9) SC intercellular lipids, which con- formation of cultured keratinocytes. The SDS treatment sist mainly of ceramide and such other components as of cultured keratinocytes significantly decreased the cholesterol esters and free fatty acids, are also known to transepidermal electrical resistance, this decrease being influence the skin barrier function. Maturation of CE is significantly ameliorated in the presence of sphingosine essential for a proper barrier function,10) and it is known or phytosphingosine, the major metabolites of glucosyl- that a decrease ofProofs ceramide causes impairment of the ceramide. These results suggest that an oral adminis- barrier function in human skin.11) tration of glucosylceramide improved the skin barrier Tight junctions (TJ)s in the granular layer of the function by up-regulating genes associated with both the epidermis also contribute to the skin barrier func- cornified envelope and tight junction formation. tion12,13) by controlling the paracellular permeability of ions and water, as well as larger molecules. TJ is formed Key words: glucosylceramide; sphingoid base; cornified by a variety of proteins, including structural trans- envelope; tight junction; skin barrier membrane components (claudins (Cldns), occludin, junctional adhesion molecules (JAMs) and tricellulin) Amorphophallus konjac (A. konjac) is a perennial and scaffolding proteins for undercoating TJ and for the plant native to eastern Asia (from Japan and China, assembly of transmembrane proteins (ZO-1, 2, 3, Mupp- south to Indonesia). It forms a large corm which 1, Magi-1 and so on),14–16) as well as some protein contains around 40% glucomannan gum,1) and is used complexes which regulate the set-up of the polarity, to prepare flour and konjac jelly. Konjac jelly is a aPKC/Par3/Par6 complex and Crb3/Pals1/Patj com- popular health food in Japan, because it has almost no plex.16,17) TJ and TJ proteins form zipper-like structures calories, but is very high in fiber content. in epithelial cells which firmly fasten adjacent cells to A. konjac is also a rich source of glucosylceramides each other, but divide between the apical space and (GCs), which are structurally constituted by sphingoid basal space to control the paracellular passage of soluble bases, long-chain fatty acids and sugar moieties, and factors. TJ proteins in mammalian skin contribute to occur in animals, fungi and plants.2,3) GCs are essential various skin functions, including barrier formation, structural components of mammalian cell membranes polarity, gene expression, proliferation, differentiation, and are mostly found at the cell surface; they participate and vesicular transport.14) in such biological functions as immunomodulation4) and Interestingly, an oral intake of GC has been reported insulin resistance.5) They also serve to maintain the to improve the skin barrier function; for example, GC y To whom correspondence should be addressed. Fax: +81-45-788-7284; E-mail: [email protected] Abbreviations: AJ, adherens junction; aPKC, atypical protein kinase C; CE, cornified envelope; Cldn, claudin; Cy, cyanine; dNHEK, differentiated normal human epidermal keratinocytes; GC, glucosylceramide; GSEA, gene set enrichment analysis; JAM, junctional adhesion molecule; Magi, membrane-associated guanylate kinase; Mupp, multiple PDZ domain protein; NHEK, normal human epidermal keratinocytes; PAGE, parametric analysis of gene set enrichment; SC, stratum corneum; SD, standard deviation; Sprr, small proline-rich protein; TER, transepithelial electrical resistance; TEWL, transepidermal water loss; TGase, transglutaminase; UV, ultraviolet light; TJ, tight junction; ZO, zonula occludens 110215-2 R. IDETA et al. improved the recovery of SC flexibility and transepider- (Thermo Fisher Scientific, Waltham, MA, USA) and an Agilent mal water loss (TEWL) in acutely barrier-perturbed Bioanalyzer (Agilent Technologies, Palo Alto, CA, USA). mice.18) A konjac extract, which contains GC, has also 19) cRNA amplification and labeling. Total RNA was amplified and improved TEWL in healthy human subjects. labeled with Cyanine 5 (Cy5) and Cyanine 3 (Cy3) by using a Low We performed a microarray analysis in this study to RNA Input linear amplification kit (Agilent Technologies) according to evaluate mRNA expression in the SDS-treated (barrier- the manufacturer’s instructions. RNAs for each sample were individ- perturbed) skin of GC-fed and control-fed mice in order ually coupled to both Cy3 and Cy5 dyes so that a dye swap comparison to clarify the mechanism for the barrier-improving effect could be made. Briefly, 500 ng of total RNA was reverse-transcribed to of orally administered GC. We evaluated two sets of double-stranded cDNA by using a poly dT-T7 promoter primer and MMLV-RT enzyme. The cDNA products were used as templates for genes associated with CE formation and TJ formation in vitro transcription to generate fluorescent cRNA by using T7 RNA and function, and calculated their average induced polymerase and Cy5-labeled or Cy3-labeled CTP. Labeled cRNAs expression ratio by GC feeding against the average were purified by using Qiagen RNeasy mini spin columns and eluted expression ratio of all genes on the microarray. We also in nuclease-free water. The cRNA quantity and cyanine incorporation confirmed the contribution of GC metabolites to TJ were determined using the Nanodrop ND-1000 and Bioanalyzer formation by examining their effect on the transepithe- instruments. lial electrical resistance (TER) of normal cultured Hybridization of sample cRNAs and data processing. Two labeled human epidermal keratinocytes. cDNA samples, one from a GC-fed mouse and the other from a control-fed mouse, were combined. Each hybridization used 825 ng of Materials and Methods labeled cRNAs that were mixed, fragmented, and hybridized at 65 C for 17 h to an Agilent 4 Â 44 K Whole Mouse Genome microarray Materials. Normal human epidermal keratinocytes (NHEK) were (Agilent 14868). After washing, the microarray was scanned with an obtained from Kurabo Co. (Osaka, Japan). NHEKs were cultured in a Agilent DNA microarray scanner. Feature Extraction software version low-Ca2þ (0.15 mM Ca2þ) medium, HuMedia-KG2 (Kurabo). Cells at 9.1.3.1 (Agilent Technologies) was used to assess the fluorescent passage three were used in this study. hybridization signals and to normalize the signals by using linear AdvanceKonjac extracts containing various concentrations of ViewGC (12%, regression and a Lowess curve-fitting technique. The reproducibility 66% and 100%) were presented by Unitika Limited (Osaka, Japan) and and reliability of each microarray were assessed by using Quality suspended in 1% of tragacanth gum (Wako Pure Chemicals Industries, Control report data in Feature Extraction. Osaka, Japan) at respective final GC concentrations of 30, 165 and 250 mg/mL. Statistical analysis. The scanned data were analyzed by using Ò Sphingoid bases, sphingosine and phytosphingosine, were pur- Genespring microarray data processing software (Agilent Technol- chased from Avanti Polar Lipids (Alabaster, AL, USA). ogies). Normalized signals were processed after first eliminating the flagged signals. Since some genes have multiple probes on the Agilent platform, gene-level expression values were calculated by using the Animals. This study was approved by the ethics committee of ‘‘Gene-level experiment’’ function in Genespring. Expression values Shiseido Research Center in accordance with the guidelines of the below 200 were floored to 200.20) The processed signal values for the National Institute of Health.
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