O-GlcNAcylation of Orphan Nuclear Receptor Estrogen-Related Receptor {gamma} Promotes Hepatic Gluconeogenesis

Estrogen-related receptor (ERR) 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 OGlcNAcylation. In this study, we demonstrate that ERR is O-GlcNAcylated by O-GlcNAc transferase in the fasted state. This stabilizes the protein by inhibiting proteasome-mediated protein degradation, increasing ERR recruitment to gluconeogenic gene promoters. Mass spectrometry identifies two serine residues (S317, S319) present in the ERR ligand-binding domain that are O-GlcNAcylated. Mutation of these residues destabilizes ERR protein and blocks the ability of ERR 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 ERR by overexpressing the deglycosylating enzyme O-GlcNAcase decreases ERR-dependent glucose production in fasted mice. We conclude that O-GlcNAcylation of ERR serves as a major signal to promote hepatic gluconeogenesis.

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