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Proc Natl Acad Sci U S A. 2017 Jun 27;114(26):E5197-E5206. doi: 10.1073/pnas.1705312114. Epub 2017 Jun 12.

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

Author information

1
Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, TX 75390-8505.
2
Merck & Co., Inc., Kenilworth, NJ 07033.
3
Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, TX 75390-8505; bruce.beutler@UTSouthwestern.edu.

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.

KEYWORDS:

SREBP; alopecia; cholesterol biosynthesis; glycerol kinase; sebocyte

PMID:
28607088
PMCID:
PMC5495269
DOI:
10.1073/pnas.1705312114
[Indexed for MEDLINE]
Free PMC Article

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