Integrated effects of multiple modulators on human liver glycogen phosphorylase<i>a</i>

Ercan-Fang, Nacide; Gannon, Mary C.; Rath, Virginia L.; Treadway, Judith L.; Taylor, Miriam R.; Nuttall, Frank Q.

doi:10.1152/ajpendo.00425.2001

Cited by 46 publications

(48 citation statements)

References 70 publications

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“…In liver, high-dose AICAR stimulates glycogenolysis (25,26) but also inhibits gluconeogenesis (31,57), lipogenesis, and cholesterol synthesis (23,35). However, enhanced glycogenolysis in muscle (32) and liver (8,22) and suppressed hepatic gluconeogenesis (31) can both be induced allosterically in vivo by raised intracellular levels of ZMP independently of a direct AMPK effect. In the most recent studies employing low-dose AICAR, HGP was enhanced in the presence of low-and high-dose insulin at eu-and hyperglycemia (8,9,38).…”

Section: Discussionmentioning

confidence: 99%

“…Such pharmacological doses would raise tissue levels of muscle ZMP to that of a direct ZMPallosteric stimulation of key intracellular enzymes of glucose metabolism (22,32,45), in addition to allosteric activation of AMPK (18). AICAR appears to activate AMPK by an allosteric ZMP-directed mechanism and not directly by activation of its upstream AMPK kinase (60).…”

Section: Impact Of Low-dose Aicarmentioning

confidence: 99%

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Impact of in vivo fatty acid oxidation blockade on glucose turnover and muscle glucose metabolism during low-dose AICAR infusion

Christopher

Rantzau²,

Chen³

et al. 2006

American Journal of Physiology-Endocrinology and Metabolism

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During the basal equilibrium period (0 -150 min), fasting dogs (n ϭ 8) were infused with [3-3 H]glucose followed by either 2-h saline or AICAR (1.5-2.0 mg ⅐ kg Ϫ1 ⅐ min Ϫ1 ) infusions. SkM was biopsied at completion of each study. On a separate day, the same protocol was undertaken after 48-h in vivo FA OX blockade. The AICAR and AICAR ϩ MP studies were repeated in three chronic alloxan-diabetic dogs. AICAR produced a transient fall in plasma glucose and increase in insulin and a small decline in free fatty acid (FFA). Parallel increases in hepatic glucose production (HGP), glucose disappearance (R d tissue), and glycolytic flux (GF) occurred, whereas metabolic clearance rate of glucose (MCR g) did not change significantly. Intracellular SkM glucose, glucose 6-phosphate, and glycogen were unchanged. Acetyl-CoA carboxylase (ACCϳpSer 221 ) increased by 50%. In the AICAR ϩ MP studies, the metabolic responses were modified: the glucose was lower over 120 min, only minor changes occurred with insulin and FFA, and HGP and R d tissue responses were markedly attenuated, but MCR g and GF increased significantly. SkM substrates were unchanged, but ACCϳpSer 221 rose by 80%. Thus low-dose AICAR leads to increases in HGP and SkM glucose uptake, which are modified by prior FA ox blockade.5-aminoimidazole-4-carboxamide-1-␤-D-ribofuranoside; 5-aminoimidazole-4-carboxamide-1-␤-D-ribosyl monophosphate; acetyl-coenzyme A carboxylase; phosphorylation; skeletal muscle; muscle biopsy; dogs AMPK ACTIVATION PLAYS A CENTRAL ROLE in the regulation of intracellular metabolism as the master switch regulating cellular ATP energy supplies by shutting down high energy-consuming pathways, such as fatty acid synthesis and cholesterol synthesis, and by activating ATP-generating pathways such as fatty acid oxidation (42, 58). Thus, through these actions, AMPK influences fuel usage and selection in and to various tissues (42). Endogenous AMPK can be activated pharmacologically by 5-aminoimidazole-4-carboxamide-1-␤-D-ribofuranoside (AICAR), which is phosphorylated in vivo to the AMP analog AICAR monophosphate (ZMP) (18). However, many of those studies employed high doses of AICAR, resulting in high tissue levels of ZMP (5,6,25,26), which might have allosterically activated glycogen phosphorylase (7), certainly in cardiac muscle (32) and in the liver (45). Nevertheless, when skeletal muscle (SkM) AMPK is activated by upstream kinases and/or by AMP allosteric effects (60), the downstream substrate acetyl-CoA carboxylase (ACC) is phosphorylated in SkM (37, 58), at Ser 221 (ACCϳpSer 221 ) (11, 52) and thereby inactivated (37, 58). Therefore, the formation of ACCϳpSer 221 represents a key sensitive marker of biological activation of AMPK in vivo (3,58). Note that the corresponding SkM site (Ser 221 ) recognized by the ACC phosphospecific rat antibody used in the assay is raised against ACC␣ϳSer 79 (11, 36, 52). The inactivation of ACC leads to reduced malonyl-CoA levels and the activation of mitochondrial carnitine palmitoyltransferase I (CPT I), which ...

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Section: Discussionmentioning

confidence: 99%

Section: Impact Of Low-dose Aicarmentioning

confidence: 99%

Impact of in vivo fatty acid oxidation blockade on glucose turnover and muscle glucose metabolism during low-dose AICAR infusion

Christopher

Rantzau²,

Chen³

et al. 2006

American Journal of Physiology-Endocrinology and Metabolism

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“…In the cell, the adenine nucleotides ATP, ADP, and AMP are tied directly or indirectly to all energetic pathways and allosterically control numerous regulatory enzymes (2)(3)(4)(5)(6). Changes in adenine nucleotides typically occur such that ATP and AMP deviate in reciprocal directions, while ADP remains constant (1).…”

Section: Introductionmentioning

confidence: 99%

Hepatic energy state is regulated by glucagon receptor signaling in mice

et al. 2009

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The hepatic energy state, defined by adenine nucleotide levels, couples metabolic pathways with energy requirements. This coupling is fundamental in the adaptive response to many conditions and is impaired in metabolic disease. We have found that the hepatic energy state is substantially reduced following exercise, fasting, and exposure to other metabolic stressors in C57BL/6 mice. Glucagon receptor signaling was hypothesized to mediate this reduction because increased plasma levels of glucagon are characteristic of metabolic stress and because this hormone stimulates energy consumption linked to increased gluconeogenic flux through cytosolic phosphoenolpyruvate carboxykinase (PEPCK-C) and associated pathways. We developed what we believe to be a novel hyperglucagonemic-euglycemic clamp to isolate an increment in glucagon levels while maintaining fasting glucose and insulin. Metabolic stress and a physiological rise in glucagon lowered the hepatic energy state and amplified AMP-activated protein kinase signaling in control mice, but these changes were abolished in glucagon receptor-null mice and mice with liver-specific PEPCK-C deletion. 129X1/Sv mice, which do not mount a glucagon response to hypoglycemia, displayed an increased hepatic energy state compared with C57BL/6 mice in which glucagon was elevated. Taken together, these data demonstrate in vivo that the hepatic energy state is sensitive to glucagon receptor activation and requires PEPCK-C, thus providing new insights into liver metabolism. IntroductionThe energy state in the cell is defined by adenine nucleotide levels and is critically coupled to nearly all metabolic processes (1). In the cell, the adenine nucleotides ATP, ADP, and AMP are tied directly or indirectly to all energetic pathways and allosterically control numerous regulatory enzymes (2-6). Changes in adenine nucleotides typically occur such that ATP and AMP deviate in reciprocal directions, while ADP remains constant (1). Such changes are the basis for using the ratio AMP/ATP (1, 7) or the equation for cellular energy charge ([ATP + (0.5 × ADP)] / [ATP + ADP + AMP]) (8, 9) as indices of the metabolic environment. Metabolic stress is thus characterized by a rise in AMP paired with a fall in ATP levels, reflecting a decrease in energy state. A fall in energy state is of considerable importance, in part due to the regulatory role of AMP/ATP ratios on AMPK activity (10). AMPK is a metabolic switch sensitive to high AMP/ATP ratios and functions to protect the energy state by inhibiting ATP-consuming processes while stimulating ATP-producing processes. (10).In most tissues, the environment is controlled to maintain a high energy state (low AMP/ATP ratio). In skeletal muscle, for example, creatine kinase limits reductions in ATP during conditions such as exercise, when energy utilization is accelerated (11,12). The liver, in contrast, lacks creatine kinase, and exercise has been shown to markedly decrease the hepatic energy state and increase the phosphorylation of AMPK (11, 13). The regulatory...

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“…Net glycogen deposition depends on the activities of glycogen synthase and phosphorylase. The activities of these enzymes are regulated not only via phosphorylation/dephosphorylation but also allosterically by some metabolic intermediates (6,17,19). The effects of fructose administration on phosphorylase activity are controversial.…”

Section: Discussionmentioning

confidence: 99%

“…Kaufmann and Froesch (27) showed an inhibition of phosphorylase by fructose 1-phosphate. ErcanFang et al (17) reported that phosphorylase was directly inhibited by high concentration of fructose 1-phosphate but not by physiological levels of the sugar. There is no evidence that glycogen synthase activity is regulated directly by changing fructose 1-phosphate content (concentration).…”

Section: Discussionmentioning

confidence: 99%

Inclusion of low amounts of fructose with an intraportal glucose load increases net hepatic glucose uptake in the presence of relative insulin deficiency in dog

Shiota¹,

Galassetti²,

Igawa³

et al. 2005

American Journal of Physiology-Endocrinology and Metabolism

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-The effect of small amounts of fructose on net hepatic glucose uptake (NHGU) during hyperglycemia was examined in the presence of insulinopenia in conscious 42-h fasted dogs. During the study, somatostatin (0.8 g ⅐ kg Ϫ1 ⅐ min Ϫ1 ) was given along with basal insulin (1.8 pmol ⅐ kg Ϫ1 ⅐ min Ϫ1 ) and glucagon (0.5 ng ⅐ kg Ϫ1 ⅐ min Ϫ1 ). After a control period, glucose (36.1 mol ⅐ kg Ϫ1 ⅐ min Ϫ1 ) was continuously given intraportally for 4 h with (2.2 mol ⅐ kg Ϫ1 ⅐ min Ϫ1 ) or without fructose. In the fructose group, the sinusoidal blood fructose level (nmol/ml) rose from Ͻ16 to 176 Ϯ 11. The infusion of glucose alone (the control group) elevated arterial blood glucose (mol/ml) from 4.3 Ϯ 0.3 to 11.2 Ϯ 0.6 during the first 2 h after which it remained at 11.6 Ϯ 0.8. In the presence of fructose, glucose infusion elevated arterial blood glucose (mol/ml) from 4.3 Ϯ 0.2 to 7.4 Ϯ 0.6 during the first 1 h after which it decreased to 6.1 Ϯ 0.4 by 180 min. With glucose infusion, net hepatic glucose balance (mol ⅐ kg Ϫ1 ⅐ min Ϫ1 ) switched from output (8.9 Ϯ 1.7 and 13.3 Ϯ 2.8) to uptake (12.2 Ϯ 4.4 and 29.4 Ϯ 6.7) in the control and fructose groups, respectively. Average NHGU (mol ⅐ kg Ϫ1 ⅐ min Ϫ1 ) and fractional glucose extraction (%) during last 3 h of the test period were higher in the fructose group (30.6 Ϯ 3.3 and 14.5 Ϯ 1.4) than in the control group (15.0 Ϯ 4.4 and 5.9 Ϯ 1.8). Glucose 6-phosphate and glycogen content (mol glucose/g) in the liver and glucose incorporation into hepatic glycogen (mol glucose/g) were higher in the fructose (218 Ϯ 2, 283 Ϯ 25, and 109 Ϯ 26, respectively) than in the control group (80 Ϯ 8, 220 Ϯ 31, and 41 Ϯ 5, respectively). In conclusion, small amounts of fructose can markedly reduce hyperglycemia during intraportal glucose infusion by increasing NHGU even when insulin secretion is compromised. diabetes mellitus; hyperglycemia; hyperinsulinemia INDIVIDUALS WITH TYPE 2 DIABETES MELLITUS exhibit excessive postprandial hyperglycemia with a defect in meal-or glucoseinduced suppression of endogenous glucose production (18,21,28,34). Several studies (21,28,34) have demonstrated that the greater net splanchnic glucose release in diabetic compared with nondiabetic subjects after glucose injection was due to excessive endogenous glucose production rather than lower initial splanchnic extraction of the ingested glucose. However, the insulin and glucose concentrations differed in the diabetic and nondiabetic subjects in all of those studies, precluding direct comparison of the efficiency of splanchnic glucose uptake. DeFronzo et al. (15) (15), found decreased splanchnic glucose uptake in diabetic subjects. It is known, however, that in the presence of euglycemia and hyperinsulinemia, there is minimal splanchnic glucose uptake (14,15,23,42). Thus the size of the signal in the above studies was very small. Hyperglycemia combined with hyperinsulinemia, on the other hand, substantially increases glucose uptake by the liver (14,23,42). Recently, Basu et al. (5) carried out a hyperglycemic and hyperins...

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Integrated effects of multiple modulators on human liver glycogen phosphorylasea

Cited by 46 publications

References 70 publications

Impact of in vivo fatty acid oxidation blockade on glucose turnover and muscle glucose metabolism during low-dose AICAR infusion

Impact of in vivo fatty acid oxidation blockade on glucose turnover and muscle glucose metabolism during low-dose AICAR infusion

Hepatic energy state is regulated by glucagon receptor signaling in mice

Inclusion of low amounts of fructose with an intraportal glucose load increases net hepatic glucose uptake in the presence of relative insulin deficiency in dog

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