Glucose-6-Phosphate–Mediated Activation of Liver Glycogen Synthase Plays a Key Role in Hepatic Glycogen Synthesis

Wilamowitz-Moellendorff, Alexander von; Hunter, Roger W.; Garcı́a-Rocha, Mar; Li, Kang; López-Soldado, Iliana; Lantier, Louise; Patel, Kashyap; Peggie, Mark; Martínez-Pons, Carlos; Voß, Martin; Calbó, Joaquim; Cohen, Patricia T.W.; Wasserman, David H.; Guinovart, Joan J.; Sakamoto, Kei

doi:10.2337/db13-0880

Cited by 86 publications

(77 citation statements)

References 39 publications

(51 reference statements)

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“…However, the effect of insulin to inhibit glycogen phosphorylase and stimulate glycogen synthase is strongly countered by the ability of low G6P levels to stimulate glycogen breakdown and limit glycogen synthesis. In fact, recent evidence indicates that the allosteric effect of G6P on glycogen synthesis and breakdown are dominant over insulin's effects (60). Thus, low hepatic G6P levels caused by high G6PC activity might limit insulin's ability to reduce glycogen breakdown, further reduce G6P levels, and limit HGP.…”

Section: Discussionmentioning

confidence: 99%

ChREBP regulates fructose-induced glucose production independently of insulin signaling

Kim¹,

Krawczyk²,

Doridot³

et al. 2016

Journal of Clinical Investigation

169

185

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It has recently been hypothesized that hepatocyte CHO metabolites (hexose-or triose-phosphates) might not only stimulate ChREBP and activate DNL, but might also serve as a signal to enhance HGP (17,18). This hypothesis derives in part from the counterintuitive observation that while ChREBP is known to stimulate glycolysis through transactivation of glycolytic genes (22), it may also transactivate expression of G6pc encoding the enzyme er, from skeletal muscle and adipose tissue enhances hepatic DNL (20). Additionally, siRNA-mediated knockdown of ChREBP in ob/ob mice decreases hepatic DNL in the setting of persistent hyperinsulinemia (21). Thus, hepatic DNL may be regulated by increased substrate delivery independently of insulin signaling. However, whether increasing intrahepatic CHO metabolites might also signal to increase glucose production has not been fully explored.

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Section: Discussionmentioning

confidence: 99%

ChREBP regulates fructose-induced glucose production independently of insulin signaling

Kim¹,

Krawczyk²,

Doridot³

et al. 2016

Journal of Clinical Investigation

169

185

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“…To investigate the effect of the murine GS-GN interaction on glycogen accumulation function in intact cells, we used cultured hepatocytes isolated from an MmGS2 knockout mouse model (23). We used an adenovirus system to infect MmGS2-deficient hepatocytes with either wild-type or mutant forms of MmGS2.…”

Section: The Gs-gn Interaction Is Required For Glycogen Accumulation Inmentioning

confidence: 99%

“…Antibodies used for SI Appendix, Glycogen Extraction and Quantification from Hepatocytes. The method described by von Wilamowitz-Moellendorff et al (23) was followed for glycogen extraction. Briefly, cells were scraped into 30% (wt/vol) KOH and the extract was heated for 15 min at 100°C.…”

Section: Glycogen Extraction and Quantification From Yeastmentioning

confidence: 99%

Structural basis for the recruitment of glycogen synthase by glycogenin

Zeqiraj

Tang

Hunter

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Glycogen is a primary form of energy storage in eukaryotes that is essential for glucose homeostasis. The glycogen polymer is synthesized from glucose through the cooperative action of glycogen synthase (GS), glycogenin (GN), and glycogen branching enzyme and forms particles that range in size from 10 to 290 nm. GS is regulated by allosteric activation upon glucose-6-phosphate binding and inactivation by phosphorylation on its N-and C-terminal regulatory tails. GS alone is incapable of starting synthesis of a glycogen particle de novo, but instead it extends preexisting chains initiated by glycogenin. The molecular determinants by which GS recognizes self-glucosylated GN, the first step in glycogenesis, are unknown. We describe the crystal structure of Caenorhabditis elegans GS in complex with a minimal GS targeting sequence in GN and show that a 34-residue region of GN binds to a conserved surface on GS that is distinct from previously characterized allosteric and binding surfaces on the enzyme. The interaction identified in the GS-GN costructure is required for GS-GN interaction and for glycogen synthesis in a cell-free system and in intact cells. The interaction of full-length GS-GN proteins is enhanced by an avidity effect imparted by a dimeric state of GN and a tetrameric state of GS. Finally, the structure of the N-and C-terminal regulatory tails of GS provide a basis for understanding phosphoregulation of glycogen synthesis. These results uncover a central molecular mechanism that governs glycogen metabolism.glucose metabolism | energy metabolism | glycogenesis | starch

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“…GS and GP are enzymatically activated by dephosphorylation and phosphorylation, respectively. The activities of these enzymes are also subject to allosteric regulation (14). The phosphorylation of GP is catalyzed by several upstream kinases, such as glycogen synthase kinase 3␤ (GSK3␤) and AMP-activated protein kinase (AMPK), whereas the dephosphorylation of GS is facilitated by protein phosphatase 1 (PP1) coupled with the glycogen-targeting regulatory subunits (15).…”

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confidence: 99%

Hepatic Overexpression of CD36 Improves Glycogen Homeostasis and Attenuates High-Fat Diet-Induced Hepatic Steatosis and Insulin Resistance

Garbacz

Miller

et al. 2016

Molecular and Cellular Biology

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The common complications in obesity and type 2 diabetes include hepatic steatosis and disruption of glucose-glycogen homeostasis, leading to hyperglycemia. Fatty acid translocase (FAT/CD36), whose expression is inducible in obesity, is known for its function in fatty acid uptake. Previous work by us and others suggested that CD36 plays an important role in hepatic lipid homeostasis, but the results have been conflicting and the mechanisms were not well understood. In this study, by using CD36-overexpressing transgenic (CD36Tg) mice, we uncovered a surprising function of CD36 in regulating glycogen homeostasis. Overexpression of CD36 promoted glycogen synthesis, and as a result, CD36Tg mice were protected from fasting hypoglycemia. When challenged with a high-fat diet (HFD), CD36Tg mice showed unexpected attenuation of hepatic steatosis, increased very low-density lipoprotein (VLDL) secretion, and improved glucose tolerance and insulin sensitivity. The HFD-fed CD36Tg mice also showed decreased levels of proinflammatory hepatic prostaglandins and 20-hydroxyeicosatetraenoic acid (20-HETE), a potent vasoconstrictive and proinflammatory arachidonic acid metabolite. We propose that CD36 functions as a protective metabolic sensor in the liver under lipid overload and metabolic stress. CD36 may be explored as a valuable therapeutic target for the management of metabolic syndrome. Individuals with metabolic syndrome or type 2 diabetes are susceptible to nonalcoholic fatty liver disease (1) and disruption of hepatic glucose and glycogen homeostasis (2). Hepatic steatosis is defined as an excess accumulation of fat in hepatocytes. Previous reports suggested that fatty acid translocase (FAT/CD36) plays an important role in hepatic lipid homeostasis (3-6). CD36 is a multiligand class B scavenger receptor with high affinity for lipids and lipid-containing ligands. CD36 is known for its lipid uptake function in macrophages, skeletal muscle, and the heart. However, the role of CD36 in hepatic lipid metabolism is still not well understood, and the available evidence is often conflicting, partly due to the lack of a reliable in vivo liver-specific gain-of-function model to specifically evaluate the function of CD36 in the liver.The basal expression of CD36 in the liver is low; however, it is highly inducible by a high-fat diet (HFD) (3). The hepatic expression of CD36 is under the transcriptional control of the nuclear receptors: liver X receptor (LXR), pregnane X receptor (PXR), peroxisome proliferator-activated receptors (PPARs), and the aryl hydrocarbon receptor (AhR) (4). Some studies have suggested that hepatic CD36, by functioning as a fatty acid transporter, has a role in the pathogenesis of hepatic steatosis (3), obesity (7, 8), and age-related hepatic steatosis (5). Furthermore, we and others reported that induction of CD36 was a common factor in fatty liver following the activation of LXR and PXR (6, 9). On the other hand, recent reports suggested that CD36 signaling might actually be beneficial in preventing fatty live...

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Glucose-6-Phosphate–Mediated Activation of Liver Glycogen Synthase Plays a Key Role in Hepatic Glycogen Synthesis

Cited by 86 publications

References 39 publications

ChREBP regulates fructose-induced glucose production independently of insulin signaling

ChREBP regulates fructose-induced glucose production independently of insulin signaling

Structural basis for the recruitment of glycogen synthase by glycogenin

Hepatic Overexpression of CD36 Improves Glycogen Homeostasis and Attenuates High-Fat Diet-Induced Hepatic Steatosis and Insulin Resistance

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