5 years ago

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

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

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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