Skin-specific regulation of SREBP processing & lipid biosynthesis by glycerol kinase 5

Duanwu Zhang, Wataru Tomisato, Lijing Su, Lei Sun, Jin Huk Choi, Zhao Zhang, Kuan Wen Wang, Xiaoming Zhan, Mihwa Choi, Xiaohong Li, Miao Tang, Jose M. Castro-Perez, Sara Hildebrand, Anne R. Murray, Eva Marie Y. Moresco, Bruce Beutler

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

The recessive N-ethyl-N-nitrosourea-induced phenotype toku is characterized by delayed hair growth, progressive hair loss, and excessive accumulation of dermal cholesterol, triglycerides, and ceramides. The toku phenotype was attributed to a null allele of Gk5, encoding glycerol kinase 5 (GK5), a skin-specific kinase expressed predominantly in sebaceous glands. GK5 formed a complex with the sterol regulatory element-binding proteins (SREBPs) through their C-Terminal regulatory domains, inhibiting SREBP processing and activation. In Gk5toku/toku mice, transcriptionally active SREBPs accumulated in the skin, but not in the liver; they were localized to the nucleus and led to elevated lipid synthesis and subsequent hair growth defects. Similar defective hair growth was observed in kinase-inactive GK5 mutant mice. Hair growth defects of homozygous toku mice were partially rescued by treatment with the HMG-CoA reductase inhibitor simvastatin. GK5 exists as part of a skin-specific regulatory mechanism for cholesterol biosynthesis, independent of cholesterol regulation elsewhere in the body.

Original languageEnglish (US)
Pages (from-to)E5197-E5206
JournalProceedings of the National Academy of Sciences of the United States of America
Volume114
Issue number26
DOIs
StatePublished - Jun 27 2017

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Sterol Regulatory Element Binding Proteins
Glycerol Kinase
Hair
Lipids
Skin
Cholesterol
Growth
Phosphotransferases
Ethylnitrosourea
Phenotype
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Sebaceous Glands
Simvastatin
Ceramides
Alopecia
Triglycerides
Alleles
Liver

Keywords

  • Alopecia
  • Cholesterol biosynthesis
  • Glycerol kinase
  • Sebocyte
  • SREBP

ASJC Scopus subject areas

  • General

Cite this

Skin-specific regulation of SREBP processing & lipid biosynthesis by glycerol kinase 5. / Zhang, Duanwu; Tomisato, Wataru; Su, Lijing; Sun, Lei; Choi, Jin Huk; Zhang, Zhao; Wang, Kuan Wen; Zhan, Xiaoming; Choi, Mihwa; Li, Xiaohong; Tang, Miao; Castro-Perez, Jose M.; Hildebrand, Sara; Murray, Anne R.; Moresco, Eva Marie Y.; Beutler, Bruce.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 114, No. 26, 27.06.2017, p. E5197-E5206.

Research output: Contribution to journalArticle

Zhang, D, Tomisato, W, Su, L, Sun, L, Choi, JH, Zhang, Z, Wang, KW, Zhan, X, Choi, M, Li, X, Tang, M, Castro-Perez, JM, Hildebrand, S, Murray, AR, Moresco, EMY & Beutler, B 2017, 'Skin-specific regulation of SREBP processing & lipid biosynthesis by glycerol kinase 5', Proceedings of the National Academy of Sciences of the United States of America, vol. 114, no. 26, pp. E5197-E5206. https://doi.org/10.1073/pnas.1705312114
Zhang, Duanwu ; Tomisato, Wataru ; Su, Lijing ; Sun, Lei ; Choi, Jin Huk ; Zhang, Zhao ; Wang, Kuan Wen ; Zhan, Xiaoming ; Choi, Mihwa ; Li, Xiaohong ; Tang, Miao ; Castro-Perez, Jose M. ; Hildebrand, Sara ; Murray, Anne R. ; Moresco, Eva Marie Y. ; Beutler, Bruce. / Skin-specific regulation of SREBP processing & lipid biosynthesis by glycerol kinase 5. In: Proceedings of the National Academy of Sciences of the United States of America. 2017 ; Vol. 114, No. 26. pp. E5197-E5206.
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abstract = "The recessive N-ethyl-N-nitrosourea-induced phenotype toku is characterized by delayed hair growth, progressive hair loss, and excessive accumulation of dermal cholesterol, triglycerides, and ceramides. The toku phenotype was attributed to a null allele of Gk5, encoding glycerol kinase 5 (GK5), a skin-specific kinase expressed predominantly in sebaceous glands. GK5 formed a complex with the sterol regulatory element-binding proteins (SREBPs) through their C-Terminal regulatory domains, inhibiting SREBP processing and activation. In Gk5toku/toku mice, transcriptionally active SREBPs accumulated in the skin, but not in the liver; they were localized to the nucleus and led to elevated lipid synthesis and subsequent hair growth defects. Similar defective hair growth was observed in kinase-inactive GK5 mutant mice. Hair growth defects of homozygous toku mice were partially rescued by treatment with the HMG-CoA reductase inhibitor simvastatin. GK5 exists as part of a skin-specific regulatory mechanism for cholesterol biosynthesis, independent of cholesterol regulation elsewhere in the body.",
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AU - Tomisato, Wataru

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AU - Sun, Lei

AU - Choi, Jin Huk

AU - Zhang, Zhao

AU - Wang, Kuan Wen

AU - Zhan, Xiaoming

AU - Choi, Mihwa

AU - Li, Xiaohong

AU - Tang, Miao

AU - Castro-Perez, Jose M.

AU - Hildebrand, Sara

AU - Murray, Anne R.

AU - Moresco, Eva Marie Y.

AU - Beutler, Bruce

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