scholarly journals Regulation of basal expression of hepatic PEPCK and G6Pase by AKT2

2020 ◽  
Vol 477 (5) ◽  
pp. 1021-1031 ◽  
Author(s):  
Lina He ◽  
Yang Li ◽  
Ni Zeng ◽  
Bangyan L. Stiles
Keyword(s):  
Fine Tuning ◽  
Creb Phosphorylation ◽  
Insulin Signal ◽  
Hepatic Glucose Metabolism ◽  
Basal Expression ◽  
Hepatic Glucose ◽  
Cyclic Amp Response Element ◽  
To Receive ◽  
Rate Limiting

Hepatic glucose metabolism signaling downstream of insulin can diverge to multiple pathways including AKT. Genetic studies suggest that AKT is necessary for insulin to suppress gluconeogenesis. To specifically address the role of AKT2, the dominant liver isoform of AKT in the regulation of gluconeogenesis genes, we generated hepatocytes lacking AKT2 (Akt2−/−). We found that, in the absence of insulin signal, AKT2 is required for maintaining the basal level expression of phosphoenolpyruvate carboxyl kinase (PEPCK) and to a lesser extent G6Pase, two key rate-limiting enzymes for gluconeogenesis that support glucose excursion due to pyruvate loading. We further showed that this function of AKT2 is mediated by the phosphorylation of cyclic AMP response element binding (CREB). Phosphorylation of CREB by AKT2 is needed for CREB to induce the expression of PEPCK and likely represents a priming event for unstimulated cells to poise to receive glucagon and other signals. The inhibition of gluconeogenesis by insulin is also dependent on the reduced FOXO1 transcriptional activity at the promoter of PEPCK. When insulin signal is absent, this activity appears to be inhibited by AKT2 in manner that is independent of its phosphorylation by AKT. Together, this action of AKT2 on FOXO1 and CREB to maintain basal gluconeogenesis activity may provide fine-tuning for insulin and glucocorticoid/glucagon to regulate gluconeogenesis in a timely manner to meet metabolic needs.

Cell volume regulates liver phosphoenolpyruvate carboxykinase and fructose-1,6-bisphosphatase genes

1998 ◽  
Vol 274 (3) ◽  
pp. G509-G517 ◽  
Author(s):  
Stephan Kaiser
Keyword(s):  
Protein Kinase ◽  
Cell Volume ◽  
Phosphoenolpyruvate Carboxykinase ◽  
Mrna Levels ◽  
Hepatic Glucose Metabolism ◽  
Hepatic Glucose ◽  
Fructose 1,6 Bisphosphatase ◽  
Dependent Protein ◽  
Altered Gene ◽  
Rate Limiting

Hypertonic-induced cell shrinkage increases glucose release in H-4-II-E rat hepatoma cells. This is paralleled by a concomitant increase in the mRNA levels of the rate-limiting enzymes of the pathway of gluconeogenesis, phospho enolpyruvate carboxykinase (PCK) and fructose-1,6-bisphosphatase (FBP), of seven- and fivefold, respectively. In contrast, hypotonic-induced swelling of the cells results in a transient decrease in PCK and FBP mRNAs to 15% and 39% of control levels. The antagonistic effects of hyper- and hypotonicity mimic the counteracting effects of adenosine 3′,5′-cyclic monophosphate (cAMP) and insulin on PCK and FBP mRNA levels. The hypertonic-induced increase in mRNA levels is due to an enhanced transcriptional rate, whereas the decrease in mRNAs caused by hypotonicity results from a decrease in transcription as well as mRNA stability. The inductive effect of hypertonicity does not require ongoing protein synthesis and acts independently of the cAMP-dependent protein kinase and protein kinase C pathways. These results suggest that cell volume changes in liver cells may play an important role in regulating hepatic glucose metabolism by altered gene expression.

The role of glucose 6-phosphate in mediating the effects of glucokinase overexpression on hepatic glucose metabolism

FEBS Journal ◽  
2006 ◽  
Vol 273 (2) ◽  
pp. 336-346 ◽  
Author(s):  
Linda Harndahl ◽  
Dieter Schmoll ◽  
Andreas W. Herling ◽  
Loranne Agius
Keyword(s):  
Glucose Metabolism ◽  
Hepatic Glucose Metabolism ◽  
Hepatic Glucose

Combined intraportal infusion of acetylcholine and adrenergic blockers augments net hepatic glucose uptake

2000 ◽  
Vol 278 (3) ◽  
pp. E544-E552 ◽  
Author(s):  
Masakazu Shiota ◽  
Patricia Jackson ◽  
Pietro Galassetti ◽  
Melanie Scott ◽  
Doss W. Neal ◽  
...  
Keyword(s):  
Glucose Uptake ◽  
Nervous Activity ◽  
Adrenergic Blockade ◽  
Test Protocol ◽  
Control Protocol ◽  
Hepatic Glucose Metabolism ◽  
Hepatic Glucose ◽  
Adrenergic Blockers ◽  
Hepatic Glucose Uptake

Portal glucose delivery in the conscious dog augments net hepatic glucose uptake (NHGU). To investigate the possible role of altered autonomic nervous activity in the effect of portal glucose delivery, the effects of adrenergic blockade and acetylcholine (ACh) on hepatic glucose metabolism were examined in 42-h-fasted conscious dogs. Each study consisted of an equilibration (−120 to −20 min), a control (−20 to 0 min), and a hyperglycemic-hyperinsulinemic period (0 to 300 min). During the last period, somatostatin (0.8 μg ⋅ kg−1⋅ min−1) was infused along with intraportal insulin (1.2 mU ⋅ kg−1⋅ min−1) and glucagon (0.5 ng ⋅ kg−1⋅ min−1). Hepatic sinusoidal insulin was four times basal (73 ± 7 μU/ml) and glucagon was basal (55 ± 7 pg/ml). Glucose was infused peripherally (0–300 min) to create hyperglycemia (220 mg/dl). In test protocol, phentolamine and propranolol were infused intraportally at 0.2 μg and 0.1 μg ⋅ kg−1⋅ min−1from 120 min on. ACh was infused intraportally at 3 μg ⋅ kg−1⋅ min−1from 210 min on. In control protocol, saline was given in place of the blockers and ACh. Hyperglycemia-hyperinsulinemia switched the net hepatic glucose balance (mg ⋅ kg−1⋅ min−1) from output (2.1 ± 0.3 and 1.1 ± 0.2) to uptake (2.8 ± 0.9 and 2.6 ± 0.6) and lactate balance (μmol ⋅ kg−1⋅ min−1) from uptake (7.5 ± 2.2 and 6.7 ± 1.6) to output (3.7 ± 2.6 and 3.9 ± 1.6) by 120 min in the control and test protocols, respectively. Therefter, in the control protocol, NHGU tended to increase slightly (3.0 ± 0.6 mg ⋅ kg−1⋅ min−1by 300 min). In the test protocol, adrenergic blockade did not alter NHGU, but ACh infusion increased it to 4.4 ± 0.6 and 4.6 ± 0.6 mg ⋅ kg−1⋅ min−1by 220 and 300 min, respectively. These data are consistent with the hypothesis that alterations in nerve activity contribute to the increase in NHGU seen after portal glucose delivery.

Role of epinephrine and norepinephrine in the metabolic response to stress hormone infusion in the conscious dog

1997 ◽  
Vol 273 (4) ◽  
pp. E674-E681 ◽  
Author(s):  
Owen P. McGuinness ◽  
Vickie Shau ◽  
Eric M. Benson ◽  
Mike Lewis ◽  
Robert T. Snowden ◽  
...  
Keyword(s):  
Metabolic Response ◽  
Glucose Production ◽  
Stress Hormone ◽  
Glucose Levels ◽  
Hepatic Glucose Metabolism ◽  
Hepatic Glucose ◽  
Response To Stress ◽  
Arteriovenous Difference ◽  
Arterial Glucose

The role of epinephrine and norepinephrine in contributing to the alterations in hepatic glucose metabolism during a 70-h stress hormone infusion (SHI) was investigated in four groups of chronically catheterized (20-h-fasted) conscious dogs. SHI increased glucagon (∼5-fold), epinephrine (∼10-fold), norepinephrine (∼10-fold), and cortisol (∼6-fold) levels. Dogs received either all the hormones (SHI; n = 5), all the hormones except epinephrine (SHI−Epi; n = 6), or all the hormones except norepinephrine (SHI−NE; n = 6). In addition, six dogs received saline only (Sal). Glucose production (Ra) and gluconeogenesis were assessed after a 70-h hormone or saline infusion with the use of tracer ([3-3H]glucose and [U-14C]alanine) and arteriovenous difference techniques. SHI increased glucose levels (108 ± 2 vs. 189 ± 10 mg/dl) and Ra(2.6 ± 0.2 vs. 4.1 ± 0.3 mg ⋅ kg−1⋅ min−1) compared with Sal. The absence of an increase in epinephrine markedly attenuated these changes (glucose and Rawere 140 ± 6 mg/dl and 2.7 ± 0.4 mg ⋅ kg−1⋅ min−1, respectively). Only 25% of the blunted rise in Racould be accounted for by an attenuation of the rise in net hepatic gluconeogenic precursor uptake (0.9 ± 0.1, 1.5 ± 0.1, and 1.1 ± 0.2 mg ⋅ kg−1⋅ min−1for Sal, SHI, and SHI−Epi, respectively). The absence of an increase in norepinephrine did not blunt the rise in arterial glucose levels, Ra, or net hepatic gluconeogenic precursor uptake (they rose to 195 ± 21 mg/dl, 3.7 ± 0.5 mg ⋅ kg−1⋅ min−1, and 1.7 ± 0.2 mg ⋅ kg−1⋅ min−1, respectively). In summary, during chronic SHI, the rise in epinephrine exerts potent stimulatory effects on glucose production principally by enhancing hepatic glycogenolysis, although the rise in circulating norepinephrine has minimal effects.

scholarly journals Exploring the Physiological Role of Transthyretin in Glucose Metabolism in the Liver

2021 ◽  
Vol 22 (11) ◽  
pp. 6073
Author(s):  
Mobina Alemi ◽  
Ângela Oliveira ◽  
Sofia C. Tavares ◽  
José Ricardo Vieira ◽  
Marco G. Alves ◽  
...  
Keyword(s):  
Glucose Metabolism ◽  
Culture Media ◽  
Physiological Role ◽  
Glucose Transporters ◽  
Mitochondrial Oxidative Stress ◽  
Mitochondrial Density ◽  
Hepatic Glucose Metabolism ◽  
Hepatic Glucose ◽  
Evolutionarily Conserved

Transthyretin (TTR), a 55 kDa evolutionarily conserved protein, presents altered levels in several conditions, including malnutrition, inflammation, diabetes, and Alzheimer’s Disease. It has been shown that TTR is involved in several functions, such as insulin release from pancreatic β-cells, recovery of blood glucose and glucagon levels of the islets of Langerhans, food intake, and body weight. Here, the role of TTR in hepatic glucose metabolism was explored by studying the levels of glucose in mice with different TTR genetic backgrounds, namely with two copies of the TTR gene, TTR+/+; with only one copy, TTR+/-; and without TTR, TTR-/-. Results showed that TTR haploinsufficiency (TTR+/-) leads to higher glucose in both plasma and in primary hepatocyte culture media and lower expression of the influx glucose transporters, GLUT1, GLUT3, and GLUT4. Further, we showed that TTR haploinsufficiency decreases pyruvate kinase M type (PKM) levels in mice livers, by qRT-PCR, but it does not affect the hepatic production of the studied metabolites, as determined by 1H NMR. Finally, we demonstrated that TTR increases mitochondrial density in HepG2 cells and that TTR insufficiency triggers a higher degree of oxidative phosphorylation in the liver. Altogether, these results indicate that TTR contributes to the homeostasis of glucose by regulating the levels of glucose transporters and PKM enzyme and by protecting against mitochondrial oxidative stress.

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