Glucose induces increases in levels of the transcriptional repressor Id2 via the hexosamine pathway.
Changes in glucose levels are known to directly alter gene expression. A number of previous studies have found that these effects are in part mediated by modulating the levels and the activity of transcription factors. We have investigated an alternative mechanism by which glucose might regulate gene expression by modulating levels of a transcriptional repressor. We have focused on Id2, which is a protein that indirectly regulates gene expression by sequestering certain transcription factors and preventing them from forming functional dimers. Id2 targets include the class A basic helix-loop-helix transcription factors and the sterol regulatory element-binding protein (SREBP)-1. We demonstrate that increases in glucose levels cause a rapid increase in levels of Id2 in J774.2 macrophages, and a number of lines of evidence indicate that this is via the hexosamine pathway because 1) the effect of glucose requires glutamine; 2) the effect of glucose is mimicked by low levels of glucosamine; 3) the effect of glucose is inhibited by azaserine, an inhibitor of glutamine:fructose-6-phosphate amidotransferase (GFAT); and 4) adenoviral mediated overexpression of GFAT increases levels of Id2. We go on to show that increases in Id2 can have functional effects on metabolic genes, because Id2 blocked the SREBP-1-induced induction of hormone-sensitive lipase (HSL) promoter activity, whereas Id2 alone does not modulate activity of the HSL promoter. In summary, these studies define a new mechanism by which glucose uses the hexosamine pathway to regulate gene expression by increasing levels of a transcriptional repressor.
Grønning
Line Mariann
LM
Department of Biochemistry and Molecular Biology, Guys Hospital, Kings College, London, United Kingdom.
Tingsabadh
Rommaneeya
R
Hardy
Kristine
K
Dalen
Knut Thomas
KT
Jat
Parmjit S
PS
Gnudi
Luigi
L
Shepherd
Peter R
PR
D000818:Animals; D001377:Azaserine / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation; D005944:Glucosamine / Q000378:metabolism; D005947:Glucose / Q000378:metabolism* / Q000494:pharmacology*; D005973:Glutamine / Q000378:metabolism; D005945:Glutamine-Fructose-6-Phosphate Transaminase (Isomerizing); D006595:Hexosamines / Q000096:biosynthesis / Q000378:metabolism; D051797:Inhibitor of Differentiation Protein 2 / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D019884:Nitrogenous Group Transferases / Q000037:antagonists & inhibitors / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism*; D002787:Sterol Esterase / Q000378:metabolism; D051780:Sterol Regulatory Element Binding Protein 1 / Q000378:metabolism
D004791:Enzyme Inhibitors; D006595:Hexosamines; C497452:Idb2 protein, mouse; D051797:Inhibitor of Differentiation Protein 2; D012097:Repressor Proteins; C497388:Srebf1 protein, mouse; D051780:Sterol Regulatory Element Binding Protein 1; D005973:Glutamine; D001377:Azaserine; D019884:Nitrogenous Group Transferases; C488523:Gfpt1 protein, mouse; D005945:Glutamine-Fructose-6-Phosphate Transaminase (Isomerizing); D002787:Sterol Esterase; D005947:Glucose; D005944:Glucosamine