Maintenance of Glucose Homeostasis through Acetylation of the Metabolic Transcriptional Coactivator PGC-1alpha

The main purpose of this proposal is to test the hypothesis that acetylation of PGC-1alpha by GCN5 and associated proteins, Pc3 and WDR18, is a key regulatory modification that controls hepatic glucose production. The major findings of this Research Technical Report are in tasks 1, 2 and 3. In task 1, we have further validated siRNAs for Pc3 and WDR18. In task 2, we have identified how WDR18 specifically interacts with GCN5 and does not interfere with the formation of the PGC-1alpha transcriptional protein complex. In Task 3, in order to identify what specific lysines are important for the PGC-1alpha function, we have also mapped the PGC-1beta lysines that are acetylated by GCN5. These experiments have pointed out to specific sites on PGC-1alpha that are also acetylated and might control hepatic glucose output. We will continue to complete the proposed tasks to understand how PGC-1alpha acetylation controls hepatic glucose production through the GCN5 complex.