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Elevated O‐GlcNAc Cycling on FOXO1A Mediates Inappropriate Hepatic Gluconeogenesis
Author(s) -
Housley Michael Patrick,
Rodgers Joseph Thomas,
Puigserver Pere,
Hart Gerald Warren
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.20.5.a955-a
Subject(s) - gluconeogenesis , phosphorylation , transactivation , foxo1 , endocrinology , transcription factor , chemistry , medicine , insulin , enzyme , microbiology and biotechnology , biology , biochemistry , protein kinase b , gene
Hepatic gluconeogenesis, which is normally suppressed by insulin, is abnormally activated in diabetes. The transcription factor FOXO1A controls expression of the gluconeogenic enzymes, PEPCK and Glucose‐6‐Phosphatase. Insulin signaling results in the nuclear exclusion of FOXO1A but post‐translational regulation of transactivation within the nucleus also occurs. Dynamic Modification of proteins by O‐GlcNAc serves as a nutrient and stress sensor and is often competitive with phosphorylation. Anti‐O‐GlcNAc antibodies and lectin studies have shown that FOXO1A is O‐GlcNAcylated. Increased flux into the UDP‐GlcNAc (donor for O‐GlcNAcylation) synthesis pathway increases FOXO1A transcriptional activity in an O‐GlcNAc transferase (OGT) dependent manner. Hyperglycemia increases O‐GlcNAcylation of FOXO1A in heptaoma cells and this increase is reversed by insulin. We conclude that hyperglycemia increases the O‐GlcNAc modification of FOXO1A resulting in paradoxically elevated hepatic gluconeogenesis, further exacerbating glucose toxicity in diabetes. Supported by NIH DK61671 and HD13563. GWH receives a share of royalties on univ. sales of CTD110.6 antibody. Arrangement managed by JHU conflict of interest policies.