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

Abstract

The recessive <i>N</i>-ethyl-<i>N</i>-nitrosourea-induced phenotype <i>toku</i> is characterized by delayed hair growth, progressive hair loss, and excessive accumulation of dermal cholesterol, triglycerides, and ceramides. The <i>toku</i> phenotype was attributed to a null allele of <i>Gk5</i>, 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 <i>Gk5</i>^{<i>toku</i>/<i>toku</i>} 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 <i>toku</i> 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.