Alteration of the 4-sphingenine scaffolds of ceramides in keratinocyte-specific Arnt-deficient mice affects skin barrier function

Satoshi Takagi, Hiromasa Tojo, Shuhei Tomita, Shigetoshi Sano, Satoshi Itami, Mariko Chikuma, Shintaro Inoue, Kyoji Horie, Gen Kondoh, Ko Hosokawa, Frank J. Gonzalez, Junji Takeda

Research output: Contribution to journalArticle

47 Citations (Scopus)

Abstract

Aryl hydrocarbon receptor nuclear translocator (ARNT), a transcription factor of the Per/AHR/ARNT/Sim family, regulates gene expression in response to environmental stimuli including xenobiotics and hypoxia. To examine its role in the epidermis, the Cre-loxP system was used to disrupt the Arnt gene in a keratinocyte-specific manner. Gene-targeted, newborn mice with almost normal appearance died neonatally of severe dehydration caused by water loss. Histology showed small changes in the architecture of cornified layers, with apparently preserved intercorneocyte lamellar structures responsible for the skin barrier function. In contrast, HPLC/ion-trap mass spectrometry revealed significant alterations in the compositions of ceramides, the major components of the lamellae. The murine epidermal ceramides normally contain 4-sphingenine and 4-hydroxysphinganine. In Arnt-null epidermis, 4-sphingenine was largely replaced by sphinganine and the amounts of ceramides with 4-hydroxysphinganine were greatly decreased, suggesting deficiency of dihydroceramide desaturases that catalyze the formation of both 4-sphingenyl and 4-hydroxysphinganyl moieties. A desaturase isoenzyme, DES-1, prefers desaturation, but DES-2 catalyzes both reactions to a similar extent. Transcript levels of Des-2, but not Des-1, were considerably decreased in cultured keratinocytes from Arnt-null epidermis. These results indicate that proper ceramide compositions through 4-desaturation regulated by ARNT are crucial for maintaining the epidermal barrier function.

Original languageEnglish
Pages (from-to)1372-1382
Number of pages11
JournalJournal of Clinical Investigation
Volume112
Issue number9
DOIs
Publication statusPublished - 2003 Nov
Externally publishedYes

Fingerprint

Sphingosine
Aryl Hydrocarbon Receptor Nuclear Translocator
Ceramides
Keratinocytes
Epidermis
Skin
Xenobiotics
Dehydration
Isoenzymes
Genes
Mass Spectrometry
Histology
Transcription Factors
High Pressure Liquid Chromatography
Ions
Gene Expression
Water

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Alteration of the 4-sphingenine scaffolds of ceramides in keratinocyte-specific Arnt-deficient mice affects skin barrier function. / Takagi, Satoshi; Tojo, Hiromasa; Tomita, Shuhei; Sano, Shigetoshi; Itami, Satoshi; Chikuma, Mariko; Inoue, Shintaro; Horie, Kyoji; Kondoh, Gen; Hosokawa, Ko; Gonzalez, Frank J.; Takeda, Junji.

In: Journal of Clinical Investigation, Vol. 112, No. 9, 11.2003, p. 1372-1382.

Research output: Contribution to journalArticle

Takagi, S, Tojo, H, Tomita, S, Sano, S, Itami, S, Chikuma, M, Inoue, S, Horie, K, Kondoh, G, Hosokawa, K, Gonzalez, FJ & Takeda, J 2003, 'Alteration of the 4-sphingenine scaffolds of ceramides in keratinocyte-specific Arnt-deficient mice affects skin barrier function', Journal of Clinical Investigation, vol. 112, no. 9, pp. 1372-1382. https://doi.org/10.1172/JCI200318513
Takagi, Satoshi ; Tojo, Hiromasa ; Tomita, Shuhei ; Sano, Shigetoshi ; Itami, Satoshi ; Chikuma, Mariko ; Inoue, Shintaro ; Horie, Kyoji ; Kondoh, Gen ; Hosokawa, Ko ; Gonzalez, Frank J. ; Takeda, Junji. / Alteration of the 4-sphingenine scaffolds of ceramides in keratinocyte-specific Arnt-deficient mice affects skin barrier function. In: Journal of Clinical Investigation. 2003 ; Vol. 112, No. 9. pp. 1372-1382.
@article{7243a77f52c44a4da390766af7bf7999,
title = "Alteration of the 4-sphingenine scaffolds of ceramides in keratinocyte-specific Arnt-deficient mice affects skin barrier function",
abstract = "Aryl hydrocarbon receptor nuclear translocator (ARNT), a transcription factor of the Per/AHR/ARNT/Sim family, regulates gene expression in response to environmental stimuli including xenobiotics and hypoxia. To examine its role in the epidermis, the Cre-loxP system was used to disrupt the Arnt gene in a keratinocyte-specific manner. Gene-targeted, newborn mice with almost normal appearance died neonatally of severe dehydration caused by water loss. Histology showed small changes in the architecture of cornified layers, with apparently preserved intercorneocyte lamellar structures responsible for the skin barrier function. In contrast, HPLC/ion-trap mass spectrometry revealed significant alterations in the compositions of ceramides, the major components of the lamellae. The murine epidermal ceramides normally contain 4-sphingenine and 4-hydroxysphinganine. In Arnt-null epidermis, 4-sphingenine was largely replaced by sphinganine and the amounts of ceramides with 4-hydroxysphinganine were greatly decreased, suggesting deficiency of dihydroceramide desaturases that catalyze the formation of both 4-sphingenyl and 4-hydroxysphinganyl moieties. A desaturase isoenzyme, DES-1, prefers desaturation, but DES-2 catalyzes both reactions to a similar extent. Transcript levels of Des-2, but not Des-1, were considerably decreased in cultured keratinocytes from Arnt-null epidermis. These results indicate that proper ceramide compositions through 4-desaturation regulated by ARNT are crucial for maintaining the epidermal barrier function.",
author = "Satoshi Takagi and Hiromasa Tojo and Shuhei Tomita and Shigetoshi Sano and Satoshi Itami and Mariko Chikuma and Shintaro Inoue and Kyoji Horie and Gen Kondoh and Ko Hosokawa and Gonzalez, {Frank J.} and Junji Takeda",
year = "2003",
month = "11",
doi = "10.1172/JCI200318513",
language = "English",
volume = "112",
pages = "1372--1382",
journal = "Journal of Clinical Investigation",
issn = "0021-9738",
publisher = "The American Society for Clinical Investigation",
number = "9",

}

TY - JOUR

T1 - Alteration of the 4-sphingenine scaffolds of ceramides in keratinocyte-specific Arnt-deficient mice affects skin barrier function

AU - Takagi, Satoshi

AU - Tojo, Hiromasa

AU - Tomita, Shuhei

AU - Sano, Shigetoshi

AU - Itami, Satoshi

AU - Chikuma, Mariko

AU - Inoue, Shintaro

AU - Horie, Kyoji

AU - Kondoh, Gen

AU - Hosokawa, Ko

AU - Gonzalez, Frank J.

AU - Takeda, Junji

PY - 2003/11

Y1 - 2003/11

N2 - Aryl hydrocarbon receptor nuclear translocator (ARNT), a transcription factor of the Per/AHR/ARNT/Sim family, regulates gene expression in response to environmental stimuli including xenobiotics and hypoxia. To examine its role in the epidermis, the Cre-loxP system was used to disrupt the Arnt gene in a keratinocyte-specific manner. Gene-targeted, newborn mice with almost normal appearance died neonatally of severe dehydration caused by water loss. Histology showed small changes in the architecture of cornified layers, with apparently preserved intercorneocyte lamellar structures responsible for the skin barrier function. In contrast, HPLC/ion-trap mass spectrometry revealed significant alterations in the compositions of ceramides, the major components of the lamellae. The murine epidermal ceramides normally contain 4-sphingenine and 4-hydroxysphinganine. In Arnt-null epidermis, 4-sphingenine was largely replaced by sphinganine and the amounts of ceramides with 4-hydroxysphinganine were greatly decreased, suggesting deficiency of dihydroceramide desaturases that catalyze the formation of both 4-sphingenyl and 4-hydroxysphinganyl moieties. A desaturase isoenzyme, DES-1, prefers desaturation, but DES-2 catalyzes both reactions to a similar extent. Transcript levels of Des-2, but not Des-1, were considerably decreased in cultured keratinocytes from Arnt-null epidermis. These results indicate that proper ceramide compositions through 4-desaturation regulated by ARNT are crucial for maintaining the epidermal barrier function.

AB - Aryl hydrocarbon receptor nuclear translocator (ARNT), a transcription factor of the Per/AHR/ARNT/Sim family, regulates gene expression in response to environmental stimuli including xenobiotics and hypoxia. To examine its role in the epidermis, the Cre-loxP system was used to disrupt the Arnt gene in a keratinocyte-specific manner. Gene-targeted, newborn mice with almost normal appearance died neonatally of severe dehydration caused by water loss. Histology showed small changes in the architecture of cornified layers, with apparently preserved intercorneocyte lamellar structures responsible for the skin barrier function. In contrast, HPLC/ion-trap mass spectrometry revealed significant alterations in the compositions of ceramides, the major components of the lamellae. The murine epidermal ceramides normally contain 4-sphingenine and 4-hydroxysphinganine. In Arnt-null epidermis, 4-sphingenine was largely replaced by sphinganine and the amounts of ceramides with 4-hydroxysphinganine were greatly decreased, suggesting deficiency of dihydroceramide desaturases that catalyze the formation of both 4-sphingenyl and 4-hydroxysphinganyl moieties. A desaturase isoenzyme, DES-1, prefers desaturation, but DES-2 catalyzes both reactions to a similar extent. Transcript levels of Des-2, but not Des-1, were considerably decreased in cultured keratinocytes from Arnt-null epidermis. These results indicate that proper ceramide compositions through 4-desaturation regulated by ARNT are crucial for maintaining the epidermal barrier function.

UR - http://www.scopus.com/inward/record.url?scp=0347986779&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0347986779&partnerID=8YFLogxK

U2 - 10.1172/JCI200318513

DO - 10.1172/JCI200318513

M3 - Article

C2 - 14597763

AN - SCOPUS:0347986779

VL - 112

SP - 1372

EP - 1382

JO - Journal of Clinical Investigation

JF - Journal of Clinical Investigation

SN - 0021-9738

IS - 9

ER -