title: Epigenetic regulation of the glucose transporter gene Slc2a1 by β-hydroxybutyrate underlies preferential glucose supply to the brain of fasted mice.
abstract: We carried out liquid chromatography-tandem mass spectrometry analysis of metabolites in mice. Those metabolome data showed that hepatic glucose content is reduced, but that brain glucose content is unaffected, during fasting, consistent with the priority given to brain glucose consumption during fasting. The molecular mechanisms for this preferential glucose supply to the brain are not fully understood. We also showed that the fasting-induced production of the ketone body β-hydroxybutyrate (β-OHB) enhances expression of the glucose transporter gene Slc2a1 (Glut1) via histone modification. Upon β-OHB treatment, Slc2a1 expression was up-regulated, with a concomitant increase in H3K9 acetylation at the critical cis-regulatory region of the Slc2a1 gene in brain microvascular endothelial cells and NB2a neuronal cells, shown by quantitative PCR analysis and chromatin immunoprecipitation assay. CRISPR/Cas9-mediated disruption of the Hdac2 gene increased Slc2a1 expression, suggesting that it is one of the responsible histone deacetylases (HDACs). These results confirm that β-OHB is a HDAC inhibitor and show that β-OHB plays an important role in fasting-induced epigenetic activation of a glucose transporter gene in the brain.
authors.affiliation: Stem Cell Project, Tokyo Metropolitan Institute of Medical Science, 2-1-6 Kamikitazawa, Setagaya-ku, Tokyo, 156-8506, Japan.
authors.forename: Kosuke
authors.initials: K
authors.lastname: Tanegashima
authors.affiliation: Cellular Genetics Laboratory, Department of Biological Sciences, Tokyo Metropolitan University, 1-1 Minami-Osawa, Hachioji-shi, Tokyo, 192-0397, Japan.
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Sato-Miyata
authors.affiliation: Cellular Genetics Laboratory, Department of Biological Sciences, Tokyo Metropolitan University, 1-1 Minami-Osawa, Hachioji-shi, Tokyo, 192-0397, Japan.
authors.forename: Masabumi
authors.initials: M
authors.lastname: Funakoshi
authors.affiliation: Center for Basic Technology Research, Tokyo Metropolitan Institute of Medical Science, 2-1-6 Kamikitazawa, Setagaya-ku, Tokyo, 156-8506, Japan.
authors.forename: Yasumasa
authors.initials: Y
authors.lastname: Nishito
authors.affiliation: Cellular Genetics Laboratory, Department of Biological Sciences, Tokyo Metropolitan University, 1-1 Minami-Osawa, Hachioji-shi, Tokyo, 192-0397, Japan.
authors.forename: Toshiro
authors.initials: T
authors.lastname: Aigaki
authors.affiliation: Stem Cell Project, Tokyo Metropolitan Institute of Medical Science, 2-1-6 Kamikitazawa, Setagaya-ku, Tokyo, 156-8506, Japan.|Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, 113-8510, Japan.
authors.forename: Takahiko
authors.initials: T
authors.lastname: Hara
mesh_terms: D020155:3-Hydroxybutyric Acid / Q000378:metabolism; D000107:Acetylation; D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology; D064113:CRISPR-Cas Systems; D042783:Endothelial Cells / Q000378:metabolism; D044127:Epigenesis, Genetic / Q000235:genetics*; D005215:Fasting; D005947:Glucose / Q000378:metabolism*; D051272:Glucose Transporter Type 1 / Q000096:biosynthesis* / Q000378:metabolism; D042421:Histone Code / Q000235:genetics; D056464:Histone Deacetylase 2 / Q000235:genetics / Q000378:metabolism*; D007657:Ketone Bodies / Q000378:metabolism; D055442:Metabolome / Q000235:genetics; D051379:Mice; D009474:Neurons / Q000378:metabolism
chemical_list: D051272:Glucose Transporter Type 1; D007657:Ketone Bodies; C495678:Slc2a1 protein, mouse; C533424:Hdac2 protein, mouse; D056464:Histone Deacetylase 2; D005947:Glucose; D020155:3-Hydroxybutyric Acid