Hepatic Glutamine Transport and Metabolism

Häussinger, Dieter

doi:10.1002/9780470123188.ch3

Cited by 39 publications

(42 citation statements)

References 199 publications

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“…Another important site of GS expression is the liver, where it is expressed in pericentral hepatocytes (14,19,53,61). Immunohistochemical examination of livers from control and PT-GS-KO mice (Fig.…”

Section: Gs Expression In Pt-gs-ko Micementioning

confidence: 99%

Proximal tubule-specific glutamine synthetase deletion alters basal and acidosis-stimulated ammonia metabolism

Lee

Osis

Handlogten

et al. 2016

American Journal of Physiology-Renal Physiology

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Lee H, Osis G, Handlogten ME, Lamers WH, Chaudhry FA, Verlander JW, Weiner ID. Proximal tubule-specific glutamine synthetase deletion alters basal and acidosis-stimulated ammonia metabolism. Am J Physiol Renal Physiol 310: F1229 -F1242, 2016. First published March 23, 2016 doi:10.1152/ajprenal.00547.2015.-Glutamine synthetase (GS) catalyzes the recycling of NH 4 ϩ with glutamate to form glutamine. GS is highly expressed in the renal proximal tubule (PT), suggesting ammonia recycling via GS could decrease net ammoniagenesis and thereby limit ammonia available for net acid excretion. The purpose of the present study was to determine the role of PT GS in ammonia metabolism under basal conditions and during metabolic acidosis. We generated mice with PT-specific GS deletion (PT-GS-KO) using Cre-loxP techniques. Under basal conditions, PT-GS-KO increased urinary ammonia excretion significantly. Increased ammonia excretion occurred despite decreased expression of key proteins involved in renal ammonia generation. After the induction of metabolic acidosis, the ability to increase ammonia excretion was impaired significantly by PT-GS-KO. The blunted increase in ammonia excretion occurred despite greater expression of multiple components of ammonia generation, including SN1 (Slc38a3), phosphate-dependent glutaminase, phosphoenolpyruvate carboxykinase, and Na ϩ -coupled electrogenic bicarbonate cotransporter. We conclude that 1) GS-mediated ammonia recycling in the PT contributes to both basal and acidosis-stimulated ammonia metabolism and 2) adaptive changes in other proteins involved in ammonia metabolism occur in response to PT-GS-KO and cause an underestimation of the role of PT GS expression.acid-base; ammonia; glutamine synthetase; proximal tubule A MAJOR FUNCTION of the kidney is to maintain acid-base homeostasis under basal conditions and in response to a variety of physiologic disturbances (29). In the kidney, ammonia 1 metabolism is a central component of basal net acid excretion, and changes in ammonia metabolism and urinary excretion are the primary components of the renal response to metabolic acidosis (62,64,66). Accordingly, understanding the molecular mechanisms of renal ammonia metabolism is central to understanding mammalian physiology and pathophysiology.Renal ammonia metabolism involves integrated functions of intrarenal ammoniagenesis and epithelial cell-specific NH 3 and NH 4 ϩ transport. Ammoniagenesis involves cellular glutamine uptake and metabolism through an enzymatic process involving phosphate-dependent glutaminase (PDG), glutamate dehydrogenase, and phosphoenolpyruvate carboxykinase (PEPCK) (7,59,60,63,65,66). Ammonia produced in the kidney undergoes regulated transport of both NH 3 and NH 4ϩ by a variety of specific proteins, including Naϩ -ATPase, and Rh glycoproteins B and C (Rhbg and Rhcg, respectively) (10,25,28,63,66,67). This integrated interaction of intrarenal ammonia production and transport facilitates highly regulated renal ammonia metabolism and excretion.However, not all ammonia...

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Section: Gs Expression In Pt-gs-ko Micementioning

confidence: 99%

Proximal tubule-specific glutamine synthetase deletion alters basal and acidosis-stimulated ammonia metabolism

Lee

Osis

Handlogten

et al. 2016

American Journal of Physiology-Renal Physiology

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confidence: 99%

“…1,2 Urea synthesis from ammonia is performed by periportal hepatocytes, whereas glutamine synthesis is restricted to a small perivenous hepatocyte population. [1][2][3][4] In functional terms, this reflects a sequential organization of hepatic ammonia-detoxicating pathways with a periportal low affinity system (urea synthesis) and a perivenous high affinity system (glutamine synthesis). 1,2 Perivenous glutamine synthetase (GS) acts as a downstream scavenger for ammonia that has escaped periportal urea synthesis and is therefore largely engaged in the maintenance of physiologically low ammonia levels in the hepatic vein.…”

mentioning

confidence: 99%

“…[1][2][3][4] In functional terms, this reflects a sequential organization of hepatic ammonia-detoxicating pathways with a periportal low affinity system (urea synthesis) and a perivenous high affinity system (glutamine synthesis). 1,2 Perivenous glutamine synthetase (GS) acts as a downstream scavenger for ammonia that has escaped periportal urea synthesis and is therefore largely engaged in the maintenance of physiologically low ammonia levels in the hepatic vein. In line with this, ammonia release by perfused rat liver is increased after selective destruction of perivenous hepatocytes by CCl 4 caused by a failure to synthesize glutamine, whereas urea synthesis is not affected.…”

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confidence: 99%

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Lipopolysaccharide-induced tyrosine nitration and inactivation of hepatic glutamine synthetase in the rat

Görg¹,

Wettstein²,

Metzger

et al. 2005

Hepatology

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Glutamine synthetase (GS) in the liver is restricted to a small perivenous hepatocyte population and plays an important role in the scavenging of ammonia that has escaped the periportal urea-synthesizing compartment. We examined the effect of a single intraperitoneal injection of lipopolysaccharide (LPS) in vivo on glutamine synthesis in rat liver. LPS injection induced expression of inducible nitric oxide synthase, which was maximal after 6 to 12 hours but returned toward control levels within 24 hours. Twenty-four hours after LPS injection, an approximately fivefold increase in tyrosine-nitrated proteins in liver was found, and GS protein expression was decreased by approximately 20%, whereas GS activity was lowered by 40% to 50%. GS was found to be tyrosine-nitrated in response to LPS, and immunodepletion of tyrosine-nitrated proteins decreased GS protein by approximately 50% but had no effect on GS activity. Together with the finding via mass spectrometry that peroxynitrite-induced inactivation of purified GS is associated with nitration of the active site tyrosine residue, our data suggest that tyrosine nitration critically contributes to inactivation of the enzyme. In line with GS inactivation, glutamine synthesis from ammonia (0.3 mmol/L) in perfused livers from 24-hour LPS-treated rats was decreased by approximately 50%, whereas urea synthesis was not significantly affected. A t the level of the liver acinus, the pathways of ammonia and glutamine metabolism are embedded in a sophisticated structural and functional organization, with considerable impact for the understanding of the liver in ammonia and pH homeostasis.

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“…T he nonessential amino acid L-glutamine (Gln) 4 is the most abundant amino acid in plasma (1), and Gln is an energy substrate for most cells (2,3). Consequently, Gln plays an important role in nitrogen and carbon-skeleton exchange among different tissues, where this amino acid fulfills many different physiological functions (4).…”

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confidence: 99%

Glutamine Protects Mice from Lethal Endotoxic Shock via a Rapid Induction of MAPK Phosphatase-1

Bang

et al. 2009

The Journal of Immunology

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The nonessential amino acid l-glutamine (Gln) is the most abundant amino acid in plasma. Clinical trials have demonstrated that Gln therapy is safe and improves clinical outcomes in critically ill patients. We have previously shown that Gln protect animals from endotoxic shock through the inhibition of cytosolic phospholipase A2 activity. In this study, we investigated how Gln regulates MAPK activation, as the molecular mechanism underlying Gln-induced cytosolic phospholipase A2 inactivation. Gln rapidly (within 10 min) inactivated p38 and JNK, but not ERK, by dephosphorylating them only when these MAPKs were phosphorylated in response to LPS in vivo as well as in vitro. Western blot analysis revealed that Gln administration resulted in rapid (∼5 min) phosphorylation and protein induction of MAP kinase phosphatase-1 (MKP-1). MKP-1 siRNA abrogated the Gln-mediated 1) inactivation of p38 and JNK, 2) induction of MKP-1, and 3) protection against endotoxic shock. The ERK inhibitor U0126 blocked Gln-induced MKP-1 phosphorylation and protein induction, as well as Gln’s protective activity against endotoxic shock. These data suggest that Gln exerts a beneficial effect on endotoxic shock by inactivating p38 and JNK via a rapid induction of MKP-1 protein in an ERK-dependent way.

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Hepatic Glutamine Transport and Metabolism

Cited by 39 publications

References 199 publications

Proximal tubule-specific glutamine synthetase deletion alters basal and acidosis-stimulated ammonia metabolism

Proximal tubule-specific glutamine synthetase deletion alters basal and acidosis-stimulated ammonia metabolism

Lipopolysaccharide-induced tyrosine nitration and inactivation of hepatic glutamine synthetase in the rat

Glutamine Protects Mice from Lethal Endotoxic Shock via a Rapid Induction of MAPK Phosphatase-1

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