碳水化合物和cAMP调节ChREBP图 |  | Although insulin and glucagon play important roles in regulating the response of cells to nutrients, cells also respond to carbohydrates through transcriptional regulation by the glucose responsive transcription factor ChREBP. ChREBP, carbohydrate responsive element binding protein, is a transcription factor that is activated by high levels of carbohydrates and repressed by cAMP. The activation of ChREBP by elevated carbohydrate levels increases the activity of genes involved in glucose metabolism such as pyruvate kinase, a rate-limiting enzyme in glycolysis, increasing the overall rate of utilization of carbohydrates. Excess carbohydrates also increase the transcription of genes that convert carbohydrates to triglycerides in the liver for storage in adipose tissue. cAMP regulates ChREBP activity by activating PKA, which phosphorylates ChREBP. Phosphorylation of ChREBP at ser(196) inactivates nuclear import and phosphorylation at Thr(666) prevents DNA binding by ChREBP. A metabolite of glucose activates protein phosphatase PP2A that then dephosphorylates both sites on ChREBP in response to increased glucose levels and increases ChREBP activity. Other pathways also regulate ChREBP activity and response to nutrients. High fat diets repress ChREBP activation by increasing AMP in liver cells, activating the AMP kinase. Phosphorylation of ChREBP by AMP kinase inactivates ChREBP and blocks glucose induction of ChREBP, linking dietary fatty acids to the regulation of carbohydrate metabolism. | |  | | | |  | | | |  | | Kawaguchi, Takumi, et al. Glucose and cAMP regulate the L-type pyruvate kinase gene by phosphorylation/dephosphorylation of the carbohydrate response element binding protein. PNAS, Vol 98(24), November 2001, 13710-15.
Kawaguchi, Takumi, et al. Mechanism for Fatty Acid Sparing Effect on Glucose-induced Transcription: regulation of carbohydrate-responsive element-binding protein by AMP-activated protein kinase. Biochem. J., vol 277(6), February 2002, 3829-35.
Qian, Jin, et al. Upstream stimulatory factor regulates PDX-1 gene expression in differentiated pancreatic beta-cells. Biochem. J., vol 341, 1999, 315-22.
Towle, Howard. Glucose and cAMP: Adversaries in the regulation of hepatic gene expression. PNAS, vol 98(24), November 2001, 13476-78.
Yamashita, Hiromi, et al. A glucose-responsive transcription factor that regulates carbohydrate metabolism in the liver. PNAS, Vol 98(16), July 2001, 9116-21. |
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