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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 feeding response by O-GlcNAcylation. (Left) Acute postprandial response. During early insulin signaling, OGT remains in the cytosol. Insulin binds to insulin receptor (IR) and triggers its autophosphorylation. Phosphorylation of IR recruits IRS1 to be phosphorylated, after which IRS1 binds to PI3K. PI3K catalyzes the production of PIP3, which recruits PDK1 to be phosphorylated and activated. Activated PDK1 phosphorylates and activates AKT, which further phosphorylates and activated downstream targets, including GSK3β and FOXO, which enhances glycogen synthesis and suppresses gluconeogenesis. (Right) Prolonged postprandial response. The insulin signaling pathway needs to be attenuated after a period of stimulation in order to maintain homeostasis. O-GlcNAcylation of insulin signal proteins contributes to the attenuation of the pathway. During prolonged insulin signaling, OGT translocates to the plasma membrane and binds with PIP3 through the PIP3-binding domain. OGT is then phosphorylated and activated by IR. Activated OGT O-GlcNAcylates key insulin signaling proteins including IRS1, PI3K, PDK1, and AKT, antagonizing the activation by phosphorylation on these proteins. These events lead to decreased glycogen synthesis and increased gluconeogenesis.
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Figure 1: Spatiotemporal regulation of feeding response by O-GlcNAcylation. (Left) Acute postprandial response. During early insulin signaling, OGT remains in the cytosol. Insulin binds to insulin receptor (IR) and triggers its autophosphorylation. Phosphorylation of IR recruits IRS1 to be phosphorylated, after which IRS1 binds to PI3K. PI3K catalyzes the production of PIP3, which recruits PDK1 to be phosphorylated and activated. Activated PDK1 phosphorylates and activates AKT, which further phosphorylates and activated downstream targets, including GSK3β and FOXO, which enhances glycogen synthesis and suppresses gluconeogenesis. (Right) Prolonged postprandial response. The insulin signaling pathway needs to be attenuated after a period of stimulation in order to maintain homeostasis. O-GlcNAcylation of insulin signal proteins contributes to the attenuation of the pathway. During prolonged insulin signaling, OGT translocates to the plasma membrane and binds with PIP3 through the PIP3-binding domain. OGT is then phosphorylated and activated by IR. Activated OGT O-GlcNAcylates key insulin signaling proteins including IRS1, PI3K, PDK1, and AKT, antagonizing the activation by phosphorylation on these proteins. These events lead to decreased glycogen synthesis and increased gluconeogenesis.

Mentions: Insulin plays a central role in glucose and lipid metabolism. After a meal, a sizable amount of insulin is rapidly released from the pancreas and is circulated to critical organs such as skeletal muscle, adipose tissue, and liver. In the liver, insulin induces acute activation of the insulin signaling cascade (acute postprandial response) followed by the attenuation of this pathway (prolonged postprandial response) (18). The temporal patterns of signal transduction are largely dictated by dynamic protein phosphorylation (19, 20). Similar to protein phosphorylation, O-GlcNAc modification can influence protein function by regulating protein–protein interaction, protein stability, nuclear-cytoplasmic shuttling, and intrinsic protein activity (21). The interplay between phosphorylation and O-GlcNAcylation has been implicated in the regulation of critical cellular processes. Here, we review the known effects of O-GlcNAc modification on insulin signal transduction in acute and prolonged postprandial responses, focusing on the role of O-GlcNAc in attenuating insulin signaling (Figure 1).


O-GlcNAc: A Bittersweet Switch in Liver.

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

Spatiotemporal regulation of feeding response by O-GlcNAcylation. (Left) Acute postprandial response. During early insulin signaling, OGT remains in the cytosol. Insulin binds to insulin receptor (IR) and triggers its autophosphorylation. Phosphorylation of IR recruits IRS1 to be phosphorylated, after which IRS1 binds to PI3K. PI3K catalyzes the production of PIP3, which recruits PDK1 to be phosphorylated and activated. Activated PDK1 phosphorylates and activates AKT, which further phosphorylates and activated downstream targets, including GSK3β and FOXO, which enhances glycogen synthesis and suppresses gluconeogenesis. (Right) Prolonged postprandial response. The insulin signaling pathway needs to be attenuated after a period of stimulation in order to maintain homeostasis. O-GlcNAcylation of insulin signal proteins contributes to the attenuation of the pathway. During prolonged insulin signaling, OGT translocates to the plasma membrane and binds with PIP3 through the PIP3-binding domain. OGT is then phosphorylated and activated by IR. Activated OGT O-GlcNAcylates key insulin signaling proteins including IRS1, PI3K, PDK1, and AKT, antagonizing the activation by phosphorylation on these proteins. These events lead to decreased glycogen synthesis and increased gluconeogenesis.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 1: Spatiotemporal regulation of feeding response by O-GlcNAcylation. (Left) Acute postprandial response. During early insulin signaling, OGT remains in the cytosol. Insulin binds to insulin receptor (IR) and triggers its autophosphorylation. Phosphorylation of IR recruits IRS1 to be phosphorylated, after which IRS1 binds to PI3K. PI3K catalyzes the production of PIP3, which recruits PDK1 to be phosphorylated and activated. Activated PDK1 phosphorylates and activates AKT, which further phosphorylates and activated downstream targets, including GSK3β and FOXO, which enhances glycogen synthesis and suppresses gluconeogenesis. (Right) Prolonged postprandial response. The insulin signaling pathway needs to be attenuated after a period of stimulation in order to maintain homeostasis. O-GlcNAcylation of insulin signal proteins contributes to the attenuation of the pathway. During prolonged insulin signaling, OGT translocates to the plasma membrane and binds with PIP3 through the PIP3-binding domain. OGT is then phosphorylated and activated by IR. Activated OGT O-GlcNAcylates key insulin signaling proteins including IRS1, PI3K, PDK1, and AKT, antagonizing the activation by phosphorylation on these proteins. These events lead to decreased glycogen synthesis and increased gluconeogenesis.
Mentions: Insulin plays a central role in glucose and lipid metabolism. After a meal, a sizable amount of insulin is rapidly released from the pancreas and is circulated to critical organs such as skeletal muscle, adipose tissue, and liver. In the liver, insulin induces acute activation of the insulin signaling cascade (acute postprandial response) followed by the attenuation of this pathway (prolonged postprandial response) (18). The temporal patterns of signal transduction are largely dictated by dynamic protein phosphorylation (19, 20). Similar to protein phosphorylation, O-GlcNAc modification can influence protein function by regulating protein–protein interaction, protein stability, nuclear-cytoplasmic shuttling, and intrinsic protein activity (21). The interplay between phosphorylation and O-GlcNAcylation has been implicated in the regulation of critical cellular processes. Here, we review the known effects of O-GlcNAc modification on insulin signal transduction in acute and prolonged postprandial responses, focusing on the role of O-GlcNAc in attenuating insulin signaling (Figure 1).

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