Maintenance of Glucose Homeostasis through Acetylation of the Metabolic Transcriptional Coactivator PGC1-alpha
Annual rept. 9 Jan 2008-8 Jan 2009
DANA-FARBER CANCER INST BOSTON MA
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The main purpose of this proposal is to test the hypothesis that acetylation of PGC-1alpha by GCN5 and associated proteins, Pc3 and WDR18, controls hepatic glucose production. The major findings of this Research Technical Report are in tasks 2, 4, 5 and 6. In task 2, we have further confirmed that Pc3 and WDR18 are part of the PGC-1alphaGCN5 complex but are not required for its assembly. In task 4, we have analyzed the effects of Pc3 and WDR18 on gluconeogenicglycolytic genes. In task 5, we have analyzed the negative effects of GCN5 on hepatic glucose metabolism. In Task 6, we have generated GCN5 and PGC-1alpha shRNA adenoviruses to knock-down these genes in liver. Overall, the experiments reported indicate that PGC-1alpha acetylation is a key chemical switch that in response to fedfasting controls liver metabolism. We will continue to complete the proposed tasks to understand how PCC-1alpha acetylation controls hepatic glucose production through the GCN5 complex.
- Genetic Engineering and Molecular Biology