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

8 Scopus citations

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

Keywords

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

ASJC Scopus subject areas

  • General

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    Zhang, D., Tomisato, W., Su, L., Sun, L., Choi, J. H., Zhang, Z., Wang, K. W., Zhan, X., Choi, M., Li, X., Tang, M., Castro-Perez, J. M., Hildebrand, S., Murray, A. R., Moresco, E. M. Y., & 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, 114(26), E5197-E5206. https://doi.org/10.1073/pnas.1705312114