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O-GlcNAc: A Bittersweet Switch in Liver.

Zhang K, Yin R, Yang X - Front Endocrinol (Lausanne) (2014)

Bottom Line: The liver is a vital organ responsible for maintaining nutrient homeostasis.These metabolic changes involve spatiotemporally co-ordinated signaling cascades.O-linked β-N-acetylglucosamine (O-GlcNAc) modification has been recognized as a nutrient sensor and regulatory molecular switch.

View Article: PubMed Central - PubMed

Affiliation: Program in Integrative Cell Signaling and Neurobiology of Metabolism, Yale University School of Medicine , New Haven, CT , USA ; Section of Comparative Medicine, Yale University School of Medicine , New Haven, CT , USA ; Department of Cellular and Molecular Physiology, Yale University School of Medicine , New Haven, CT , USA.

ABSTRACT
The liver is a vital organ responsible for maintaining nutrient homeostasis. After a meal, insulin stimulates glycogen and lipid synthesis in the liver; in the fasted state, glucagon induces gluconeogenesis and ketogenesis, which produce glucose and ketone bodies for other tissues to use as energy sources. These metabolic changes involve spatiotemporally co-ordinated signaling cascades. O-linked β-N-acetylglucosamine (O-GlcNAc) modification has been recognized as a nutrient sensor and regulatory molecular switch. This review highlights mechanistic insights into spatiotemporal regulation of liver metabolism by O-GlcNAc modification and discusses its pathophysiological implications in insulin resistance, non-alcoholic fatty liver disease, and fibrosis.

No MeSH data available.


Related in: MedlinePlus

Spatiotemporal regulation of fasting response by O-GlcNAcylation. (Left) During short-term fasting, glucagon stimulates gluconeogenesis by enhancing the activity of CREB. Phosphorylation of CREB by PKA directly promotes gluconeogenic gene expression. Additionally, OGT can induce gluconeogenesis by O-GlcNAcylating CRTC2, the co-activator of CREB. When CRTC2 is dephosphorylated and then O-GlcNAcylated at the same site, it translocates into the nucleus and binds to CREB to induce gluconeogenesis. (Right) In prolonged fasting, OGT targets PGC-1α via a complex with HCF-1. Both PGC-1α and HCF-1 can be O-GlcNAcylated. O-GlcNAcylated PGC-1α helps recruit OGT to glycosylate and activate FOXO1, which further promotes hepatic glucose production.
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Figure 2: Spatiotemporal regulation of fasting response by O-GlcNAcylation. (Left) During short-term fasting, glucagon stimulates gluconeogenesis by enhancing the activity of CREB. Phosphorylation of CREB by PKA directly promotes gluconeogenic gene expression. Additionally, OGT can induce gluconeogenesis by O-GlcNAcylating CRTC2, the co-activator of CREB. When CRTC2 is dephosphorylated and then O-GlcNAcylated at the same site, it translocates into the nucleus and binds to CREB to induce gluconeogenesis. (Right) In prolonged fasting, OGT targets PGC-1α via a complex with HCF-1. Both PGC-1α and HCF-1 can be O-GlcNAcylated. O-GlcNAcylated PGC-1α helps recruit OGT to glycosylate and activate FOXO1, which further promotes hepatic glucose production.

Mentions: O-GlcNAcylation of many gluconeogenic transcription factors and cofactors has been reported to promote glucose production in the liver. OGT can induce hepatic gluconeogenesis by O-GlcNAcylation of CRTC2, the co-activator of CREB. At basal levels, CRTCs are phosphorylated at Ser 70 and Ser 171 by salt-inducible kinases (SIKs) and other members of the AMP-activated protein kinase (AMPK) family and are sequestered in the cytoplasm by 14-3-3 proteins (46). In response to cAMP and calcium signals, CRTC2 is dephosphorylated and O-GlcNAcylated at the same site. This promotes CRTC2 translocation into the nucleus and binding to CREB, which induce gluconeogenesis (47) (Figure 2).


O-GlcNAc: A Bittersweet Switch in Liver.

Zhang K, Yin R, Yang X - Front Endocrinol (Lausanne) (2014)

Spatiotemporal regulation of fasting response by O-GlcNAcylation. (Left) During short-term fasting, glucagon stimulates gluconeogenesis by enhancing the activity of CREB. Phosphorylation of CREB by PKA directly promotes gluconeogenic gene expression. Additionally, OGT can induce gluconeogenesis by O-GlcNAcylating CRTC2, the co-activator of CREB. When CRTC2 is dephosphorylated and then O-GlcNAcylated at the same site, it translocates into the nucleus and binds to CREB to induce gluconeogenesis. (Right) In prolonged fasting, OGT targets PGC-1α via a complex with HCF-1. Both PGC-1α and HCF-1 can be O-GlcNAcylated. O-GlcNAcylated PGC-1α helps recruit OGT to glycosylate and activate FOXO1, which further promotes hepatic glucose production.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4269194&req=5

Figure 2: Spatiotemporal regulation of fasting response by O-GlcNAcylation. (Left) During short-term fasting, glucagon stimulates gluconeogenesis by enhancing the activity of CREB. Phosphorylation of CREB by PKA directly promotes gluconeogenic gene expression. Additionally, OGT can induce gluconeogenesis by O-GlcNAcylating CRTC2, the co-activator of CREB. When CRTC2 is dephosphorylated and then O-GlcNAcylated at the same site, it translocates into the nucleus and binds to CREB to induce gluconeogenesis. (Right) In prolonged fasting, OGT targets PGC-1α via a complex with HCF-1. Both PGC-1α and HCF-1 can be O-GlcNAcylated. O-GlcNAcylated PGC-1α helps recruit OGT to glycosylate and activate FOXO1, which further promotes hepatic glucose production.
Mentions: O-GlcNAcylation of many gluconeogenic transcription factors and cofactors has been reported to promote glucose production in the liver. OGT can induce hepatic gluconeogenesis by O-GlcNAcylation of CRTC2, the co-activator of CREB. At basal levels, CRTCs are phosphorylated at Ser 70 and Ser 171 by salt-inducible kinases (SIKs) and other members of the AMP-activated protein kinase (AMPK) family and are sequestered in the cytoplasm by 14-3-3 proteins (46). In response to cAMP and calcium signals, CRTC2 is dephosphorylated and O-GlcNAcylated at the same site. This promotes CRTC2 translocation into the nucleus and binding to CREB, which induce gluconeogenesis (47) (Figure 2).

Bottom Line: The liver is a vital organ responsible for maintaining nutrient homeostasis.These metabolic changes involve spatiotemporally co-ordinated signaling cascades.O-linked β-N-acetylglucosamine (O-GlcNAc) modification has been recognized as a nutrient sensor and regulatory molecular switch.

View Article: PubMed Central - PubMed

Affiliation: Program in Integrative Cell Signaling and Neurobiology of Metabolism, Yale University School of Medicine , New Haven, CT , USA ; Section of Comparative Medicine, Yale University School of Medicine , New Haven, CT , USA ; Department of Cellular and Molecular Physiology, Yale University School of Medicine , New Haven, CT , USA.

ABSTRACT
The liver is a vital organ responsible for maintaining nutrient homeostasis. After a meal, insulin stimulates glycogen and lipid synthesis in the liver; in the fasted state, glucagon induces gluconeogenesis and ketogenesis, which produce glucose and ketone bodies for other tissues to use as energy sources. These metabolic changes involve spatiotemporally co-ordinated signaling cascades. O-linked β-N-acetylglucosamine (O-GlcNAc) modification has been recognized as a nutrient sensor and regulatory molecular switch. This review highlights mechanistic insights into spatiotemporal regulation of liver metabolism by O-GlcNAc modification and discusses its pathophysiological implications in insulin resistance, non-alcoholic fatty liver disease, and fibrosis.

No MeSH data available.


Related in: MedlinePlus