| Budget Amount *help |
¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000)
Fiscal Year 2014: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
Fiscal Year 2013: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
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| Outline of Final Research Achievements |
We show that carbohydrate response element binding protein (ChREBP), a glucose-regulated transcription factor, is O-glycosylated by OGT, leading to increased ChREBP levels, owing to decreased ubiquitination. Conversely, expression of O-GlcNAcase (GCA) in hepatocytes decreases ChREBP O-glycosylation, thus reducing its protein levels. FoxO1, a downstream effector of insulin signaling, has been known to regulate glucose metabolism in liver. We show here that FoxO1 overexpression inhibits ChREBP O-glycosylation in hepatocytes, thus reducing ChREBP levels. Conversely, conditional FoxO1 knockout in liver results in increased levels of O-glycosylated ChREBP, even in the fasted state. O-glycosylation is an important mechanism to regulate ChREBP function, and that FoxO1 is required for ChREBP O-glycosylation. We propose that FoxO1 is the shared signaling element linking glucose- and insulin-activated pathways to regulate hepatic glucose metabolism.
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