Role of pancreatic L-asparagine synthetase in homeostasis of L-asparagine.

Milman, Harry A.; Cooney, David A.; Young, D M

doi:10.1152/ajpendo.1979.236.6.e746

Cited by 8 publications

(6 citation statements)

References 18 publications

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“…Similar changes were found after infusing aspartate at 3 mmol/kg body wt. per h. These findings may be explained by the recent finding of Milman et al (1979), who reported that after injection of [14Clasparagine and ['4Claspartate into mice, the majority of the radioactivity was recovered in pancreas, small intestine and lung, and only small amounts in liver. In contrast alanine is taken up avidly by liver.…”

Section: Discussionmentioning

confidence: 84%

A possible mechanism for the anti-ketogenic action of alanine in the rat

Nosadini

Datta

Hodson

et al. 1980

Biochemical Journal

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1. The anti-ketogenic effect of alanine has been studied in normal starved and diabetic rats by infusing l-alanine for 90min in the presence of somatostatin (10mug/kg body wt. per h) to suppress endogenous insulin and glucagon secretion. 2. Infusion of alanine at 3mmol/kg body wt. per h caused a 70+/-11% decrease in [3-hydroxybutyrate] and a 58+/-9% decrease in [acetoacetate] in 48h-starved rats. [Glucose] and [lactate] increased, but [non-esterified fatty acid], [glycerol] and [3-hydroxybutyrate]/[acetoacetate] were unchanged. 3. Infusion of alanine at 1mmol/kg body wt. per h caused similar decreases in [ketone body] (3-hydroxybutyrate plus acetoacetate) in 24h-starved normal and diabetic rats, but no change in other blood metabolites. 4. Alanine [3mmol/kg body wt. per h] caused a 72+/-9% decrease in the rate of production of ketone bodies and a 57+/-8% decrease in disappearance rate as assessed by [3-(14)C]acetoacetate infusion. Metabolic clearance was unchanged, indicating that the primary effect of alanine was inhibition of hepatic ketogenesis. 5. Aspartate infusion at 6mmol/kg body wt. per h had similar effects on blood ketone-body concentrations in 48h-starved rats. 6. Alanine (3mmol/kg body wt. per h) caused marked increases in hepatic glutamate, aspartate, malate, lactate and citrate, phosphoenolpyruvate, 2-phosphoglycerate and glucose concentrations and highly significant decreases in [3-hydroxybutyrate] and [acetoacetate]. Calculated [oxaloacetate] was increased 75%. 7. Similar changes in hepatic [malate], [aspartate] and [ketone bodies] were found after infusion of 6mmol of aspartate/kg body wt. per h. 8. It is suggested that the anti-ketogenic effect of alanine is secondary to an increase in hepatic oxaloacetate and hence citrate formation with decreased availability of acetyl-CoA for ketogenesis. The reciprocal negative-feedback cycle of alanine and ketone bodies forms an important non-hormonal regulatory system.

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Section: Discussionmentioning

confidence: 84%

A possible mechanism for the anti-ketogenic action of alanine in the rat

Nosadini

Datta

Hodson

et al. 1980

Biochemical Journal

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“…The specific activity of ASNS in mouse tissues is highest in the pancreas, with exocrine cells contributing Ͼ99% of the activity to provide asparagine for important pancreatic proteins, namely, digestive enzymes that contain asparaginyl residues (39). However, the pancreas does not contribute to circulating concentrations of asparagine (40), suggesting that the pancreas may be insensitive to and/or buffered from changes in serum asparagine. We speculate that eIF2 phosphorylation is briefly activated in response to glutamine depletion, but the study end point missed the window of detection.…”

Section: Discussionmentioning

confidence: 99%

General control nonderepressible 2 deletion predisposes to asparaginase-associated pancreatitis in mice

Phillipson-Weiner

Mirek

Wang

et al. 2016

American Journal of Physiology-Gastrointestinal and Liver Physi

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Treatment with the antileukemic agent asparaginase can induce acute pancreatitis, but the pathophysiology remains obscure. In the liver of mice, eukaryotic initiation factor 2 (eIF2) kinase general control nonderepressible 2 (GCN2) is essential for mitigating metabolic stress caused by asparaginase. We determined the consequences of asparaginase treatment on the pancreata of wild-type (WT, GCN2-intact) and GCN2-deleted (ΔGcn2) mice. Mean pancreas weights in ΔGcn2 mice treated with asparaginase for 8 days were increased (P < 0.05) above all other groups. Histological examination revealed acinar cell swelling and altered staining of zymogen granules in ΔGcn2, but not WT, mice. Oil Red O staining and measurement of pancreas triglycerides excluded lipid accumulation as a contributor to acini appearance. Instead, transmission electron microscopy revealed dilatation of the endoplasmic reticulum (ER) and accumulation of autophagic vacuoles in the pancreas of ΔGcn2 mice treated with asparaginase. Consistent with the idea that loss of GCN2 in a pancreas exposed to asparaginase induced ER stress, phosphorylation of protein kinase R-like ER kinase (PERK) and its substrate eIF2 was increased in the pancreas of asparaginase-treated ΔGcn2 mice. In addition, mRNA expression of PERK target genes, activating transcription factors 4, 3, and 6 (Atf4, Atf3, and Atf6), fibroblast growth factor 21 (Fgf21), heat shock 70-kDa protein 5 (Hspa5), and spliced Xbp1 (sXbp1), as well as pancreas mass, was elevated in the pancreas of asparaginase-treated ΔGcn2 mice. Furthermore, genetic markers of oxidative stress [sirtuin (Sirt1)], inflammation [tumor necrosis factor-α (Tnfα)], and pancreatic injury [pancreatitis-associated protein (Pap)] were elevated in asparaginase-treated ΔGcn2, but not WT, mice. These data indicate that loss of GCN2 predisposes the exocrine pancreas to a maladaptive ER stress response and autophagy during asparaginase treatment and represent a genetic basis for development of asparaginase-associated pancreatitis.

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“…53 It has long been speculated that asparaginase triggers pancreatitis in patients who have an intrinsic inability to counteract depletion of pancreatic asparagine. 54 A better understanding of the mechanisms underlying pancreatitis from these types of medications will (1) provide guidance of which patients to prescribe the medication, (2) help devise preventatives or rescue therapies, and, on a broader level, (3) will elucidate the intricate physiology of nutrient handling in the translationally active exocrine pancreas. 55 To categorically design useful decision-making guidelines for medicationassociated pancreatitis, what also is required is a comprehensive analysis of patient information in the form of a database framework that resembles the existing Drug-Induced Liver Injury Network.…”

Section: Medicationsmentioning

confidence: 99%

Pancreatitis in Children

2019

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Acute, acute recurrent, and chronic forms of pancreatitis have been increasingly diagnosed in children in the past 2 decades. Risk factors in the pediatric group are broad and appear to be strikingly different compared with the adult cohort. However, the disease burden and impact on quality of life are surprisingly similar in children and adults. This review summarizes the definitions, epidemiology, risk factors, diagnosis, and management of pediatric pancreatitis, identifies features that are unique to the childhood-onset disease, identifies gaps, and proposes recommendations for future opportunities.

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Role of pancreatic L-asparagine synthetase in homeostasis of L-asparagine.

Cited by 8 publications

References 18 publications

A possible mechanism for the anti-ketogenic action of alanine in the rat

A possible mechanism for the anti-ketogenic action of alanine in the rat

General control nonderepressible 2 deletion predisposes to asparaginase-associated pancreatitis in mice

Pancreatitis in Children

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