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

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 sk...

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Published inProceedings of the National Academy of Sciences - PNAS Vol. 114; no. 26; pp. E5197 - E5206
Main Authors 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
Format Journal Article
LanguageEnglish
Published United States National Academy of Sciences 27.06.2017
SeriesPNAS Plus
Subjects
Biological Sciences
Biosynthesis
Cholesterol
Defects
Ethyl nitrosourea
Genotype & phenotype
Glands
Glycerol
Glycerol kinase
Hair
Hydroxymethylglutaryl-CoA reductase
Kinases
Lipids
Liver
Mice
Nuclei
PNAS Plus
Proteins
Regulatory mechanisms (biology)
Regulatory sequences
Rodents
Sebaceous glands
Simvastatin
Skin
Sterol regulatory element-binding protein
Transcription
Triglycerides
SREBP
alopecia
sebocyte
cholesterol biosynthesis
glycerol kinase
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Summary: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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Author contributions: D.Z., W.T., X.Z., and B.B. designed research; D.Z., W.T., L. Su, L. Sun, J.H.C., Z.Z., K.-w.W., X.Z., M.C., X.L., M.T., and J.M.C.-P. performed research; D.Z., W.T., X.Z., J.M.C.-P., S.H., and B.B. analyzed data; and D.Z., A.R.M., E.M.Y.M., and B.B. wrote the paper.
1Present address: Group II, Frontier Research Laboratories, R&D Division, Daiichi Sankyo Co., Ltd., Shinagawa-ku, Tokyo 140-8710, Japan.
2Present address: Waters Corporation, Milford, MA 01757.
Reviewers: D.L.K., National Institutes of Health; and C.C.Z., Theodor Fontane Medical University of Brandenburg, Dessau Medical Center.
Contributed by Bruce Beutler, May 9, 2017 (sent for review March 30, 2017; reviewed by Daniel L. Kastner and Christos C. Zouboulis)
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.1705312114