| First Author | Misra J | Year | 2016 |
| Journal | Diabetes | Volume | 65 |
| Issue | 10 | Pages | 2835-48 |
| PubMed ID | 27335230 | Mgi Jnum | J:246629 |
| Mgi Id | MGI:5922518 | Doi | 10.2337/db15-1523 |
| Citation | Misra J, et al. (2016) O-GlcNAcylation of Orphan Nuclear Receptor Estrogen-Related Receptor gamma Promotes Hepatic Gluconeogenesis. Diabetes 65(10):2835-48 |
| abstractText | Estrogen-related receptor gamma (ERRgamma) is a major positive regulator of hepatic gluconeogenesis. Its transcriptional activity is suppressed by phosphorylation signaled by insulin in the fed state, but whether posttranslational modification alters its gluconeogenic activity in the fasted state is not known. Metabolically active hepatocytes direct a small amount of glucose into the hexosamine biosynthetic pathway, leading to protein O-GlcNAcylation. In this study, we demonstrate that ERRgamma is O-GlcNAcylated by O-GlcNAc transferase in the fasted state. This stabilizes the protein by inhibiting proteasome-mediated protein degradation, increasing ERRgamma recruitment to gluconeogenic gene promoters. Mass spectrometry identifies two serine residues (S317, S319) present in the ERRgamma ligand-binding domain that are O-GlcNAcylated. Mutation of these residues destabilizes ERRgamma protein and blocks the ability of ERRgamma to induce gluconeogenesis in vivo. The impact of this pathway on gluconeogenesis in vivo was confirmed by the observation that decreasing the amount of O-GlcNAcylated ERRgamma by overexpressing the deglycosylating enzyme O-GlcNAcase decreases ERRgamma-dependent glucose production in fasted mice. We conclude that O-GlcNAcylation of ERRgamma serves as a major signal to promote hepatic gluconeogenesis. |
