| Autor: |
Jagannath Misra, Don-Kyu Kim, Yoon Seok Jung, Han Byeol Kim, Yong-Hoon Kim, Eun-Kyung Yoo, Byung Gyu Kim, Sunghoon Kim, In-Kyu Lee, Harris, Robert A., Jeong-Sun Kim, Chul-Ho Lee, Jin Won Cho, Hueng-Sik Choi, Misra, Jagannath, Kim, Don-Kyu, Jung, Yoon Seok, Kim, Han Byeol, Kim, Yong-Hoon, Yoo, Eun-Kyung |
| Předmět: |
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| Zdroj: |
Diabetes; Oct2016, Vol. 65 Issue 10, p2835-2848, 14p, 4 Diagrams, 2 Graphs |
| Abstrakt: |
Estrogen-related receptor γ (ERRγ) 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 ERRγ is O-GlcNAcylated by O-GlcNAc transferase in the fasted state. This stabilizes the protein by inhibiting proteasome-mediated protein degradation, increasing ERRγ recruitment to gluconeogenic gene promoters. Mass spectrometry identifies two serine residues (S317, S319) present in the ERRγ ligand-binding domain that are O-GlcNAcylated. Mutation of these residues destabilizes ERRγ protein and blocks the ability of ERRγ 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 ERRγ by overexpressing the deglycosylating enzyme O-GlcNAcase decreases ERRγ-dependent glucose production in fasted mice. We conclude that O-GlcNAcylation of ERRγ serves as a major signal to promote hepatic gluconeogenesis. [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
| Externí odkaz: |
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