O-GlcNAcylation of orphan nuclear receptor estrogen-related receptor γ promotes hepatic gluconeogenesis

Abstract

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