TY - JOUR
T1 - Skin-specific regulation of SREBP processing & lipid biosynthesis by glycerol kinase 5
AU - Zhang, Duanwu
AU - Tomisato, Wataru
AU - Su, Lijing
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
N1 - Funding Information:
This work was supported by NIH Grant U19 AI100627.
PY - 2017/6/27
Y1 - 2017/6/27
N2 - 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.
AB - 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.
KW - Alopecia
KW - Cholesterol biosynthesis
KW - Glycerol kinase
KW - SREBP
KW - Sebocyte
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U2 - 10.1073/pnas.1705312114
DO - 10.1073/pnas.1705312114
M3 - Article
C2 - 28607088
AN - SCOPUS:85021433012
SN - 0027-8424
VL - 114
SP - E5197-E5206
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 26
ER -