Clarification of novel activation mechanism of transcription factor ChREBP under diabetic condition

2010 Fiscal Year Final Research Report

• Project/Area Number: 21700710
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Single-year Grants
• Research Field: Applied health science
• Research Institution: Hyogo College of Medicine
• Principal Investigator: SAKIYAMA Haruhiko Hyogo College of Medicine, 医学部, 助教 (30508958)
• Project Period (FY): 2009 – 2010
• Keywords: 転写因子 / ChREBP / 肥満 / 糖尿病 / 細胞内局在

Research Abstract

The carbohydrate response element-binding protein (ChREBP) functions as a transcription factor in mediating the glucose-activated gene expression of multiple liver enzymes, which are responsible for converting excess carbohydrate to storage fat. ChREBP is translocated into the nucleus in response to high glucose levels, and then up-regulates transcriptional activity. Although this glucose activation of ChREBP is generally observed only in liver cells, overexpression of wild type max-like protein X (Mlx), but not an inactive mutant Mlx, resulted in the exhibition of the ChREBP functions also in a human kidney cell line. Because high glucose conditions induce the glycosylation of cellular proteins, the effect of O-linked GlcNAc modification on ChREBP functions was examined. Treatment with an O-GlcNAcase inhibitor (PUGNAc), which increases the O-linked GlcNAc modification of cellular proteins, caused an increase in the glucose response of ChREBP. In contrast, treatment with a glutamine fructose amidotransferase inhibitor (DON), which decreases O-GlcNAcylation by inhibiting the hexosamine biosynthetic pathway, completely blocked the glucose response of ChREBP. These results suggest that the O-linked glycosylation of ChREBP itself or other proteins that regulate ChREBP is essential for the production of functional ChREBP.

Research Products

• [Journal Article] The role of O-linked GlcNAc modification on the glucose response of ChREBP. (2010)
  • Author(s): Sakiyama,H., Fujiwara,N., Noguchi,T., Eguchi,H., Yoshihara,D., Uyeda,K., Suzuki, K
  • Journal Title: Biochem, Biophys. Res. Commun. 402 Pages: 784-789
  • Peer Reviewed
• [Presentation] 転写因子ChREBPの活性化に及ぼすO-GlcNAc修飾およびMlxの役割 (2010)
  • Author(s): 崎山晴彦, 藤原範子, 江口裕伸, 吉原大作, Ko Uyeda, 鈴木敬一郎
  • Organizer: 第83回日本生化学会大会第33回日本分子生物学会、合同大会
  • Place of Presentation: 神戸
  • Year and Date: 2010-12-07
• [Presentation] Mlxの結合が転写因子ChREBPの細胞内局在に及ぼす影響の検討 (2009)
  • Author(s): 崎山晴彦, 深澤昌史, 藤原範子, 江口裕伸, 横江俊一, 吉原大作, 鈴木敬一郎
  • Organizer: 第82回日本生化学会大会
  • Place of Presentation: 神戸
  • Year and Date: 2009-10-23
• [Presentation] 14-3-3の結合が転写因子ChREBPの核移行に及ぼす影響の検討 (2009)
  • Author(s): 崎山晴彦, 深澤昌史, 水口博之, 藤原範子, 江口裕伸, 横江俊一, 吉原大作, Ko Uyeda, 鈴木敬一郎
  • Organizer: 第56回日本生化学会近畿支部例会
  • Place of Presentation: 大阪
  • Year and Date: 2009-07-18