Glucagon Regulates Hepatic Inducible Nitric Oxide Synthesis in Vivo

Harbrecht, Brian G.; Perpetua, Michelle; Fulmer, Melissa L.; Zhang, Baochun

doi:10.1097/01.shk.0000131579.22409.33

Cited by 19 publications

(15 citation statements)

References 36 publications

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“…We cannot exclude the possibility, though, that FK506 regulates pathways other than calcineurin or inhibits other phosphatases. Our current results are consistent with our previous work demonstrating that glucagon and cAMP, compounds known to increase Ca 2+ in hepatocytes, suppress iNOS expression (6,8,13). In hepatocytes, adrenergic agents also increase intracellular Ca 2+ and Collins demonstrated that adrenergic agonists suppress hepatocyte iNOS expression (34).…”

Section: Discussionsupporting

confidence: 94%

“…We have previously demonstrated that hepatocyte iNOS is regulated by cyclic adenosine monophosphate (cAMP) and the cAMP-elevating hormone glucagon (6–8). Cyclic cAMP and glucagon have profound effects on hepatocyte function by regulating glucose metabolism and expression of phosphoenolpyruvate carboxykinase (PEPCK), the rate-limiting enzyme in hepatic gluconeogenesis (9).…”

Section: Introductionmentioning

confidence: 99%

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Calcium-mediated signaling and calmodulin-dependent kinase regulate hepatocyte-inducible nitric oxide synthase expression

Zhang¹,

Crankshaw²,

Nesemeier³

et al. 2015

Journal of Surgical Research

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Background Nitric oxide synthase (iNOS) is induced in hepatocytes by shock and inflammatory stimuli. Excessive NO from iNOS mediates shock-induced hepatic injury and death so understanding the regulation of iNOS will help elucidate the pathophysiology of septic shock. In vitro, cytokines induce iNOS expression through activation of signaling pathways including mitogen-activated protein kinases and Nuclear Factor κB. Cytokines also induce calcium (Ca2+) mobilization and activate calcium-mediated intracellular signaling pathways, typically through activation of calmodulin-dependent kinases (CaMK). Calcium regulates NO production in macrophages but the role of calcium and calcium-mediated signaling in hepatocyte iNOS expression has not been defined. Materials and Methods Primary rat hepatocytes were isolated, cultured, and induced to produce NO with proinflammatory cytokines. Calcium mobilization and Ca2+-mediated signaling were altered with ionophore, Ca2+ channel blockers, and inhibitors of CaMK. Results The Ca2+ ionophore A23187 suppressed cytokine-stimulated NO production while EGTA and nifedipine increased NO production, iNOS mRNA, and iNOS protein expression. Inhibition of CaMK with KN93 and CBD increased NO production but the calcineurin inhibitor FK 506 decreased iNOS expression. Conclusions These data demonstrate that calcium-mediated signaling regulates hepatocyte iNOS expression and does so through a mechanism independent of calcineurin. Changes in intracellular calcium levels may regulate iNOS expression during hepatic inflammation induced by pro-inflammatory cytokines.

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Section: Discussionsupporting

confidence: 94%

Section: Introductionmentioning

confidence: 99%

Calcium-mediated signaling and calmodulin-dependent kinase regulate hepatocyte-inducible nitric oxide synthase expression

Zhang¹,

Crankshaw²,

Nesemeier³

et al. 2015

Journal of Surgical Research

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“…Increases in cAMP, such as occur during times of metabolic stress when circulating glucagon levels are high, protect cultured hepatocytes from apoptosis due to several stimuli including bile acids, Fas, and TNF-␣ (12,21,36,61). In vivo, oral administration of phosphodiesterase inhibitors (18,32) or ␤ 2 -adrenergic agonists (1), agents that increase hepatic cAMP levels, or parenteral administration of glucagon (24) or cell-permeable cAMP analogs (28,57) protect against toxic and ischemic hepatic injury in laboratory animals. Furthermore, it is known that the diseased liver develops dysregulations in cAMP signaling that contribute to increased hepatobiliary damage (15,19,20,27,35).…”

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confidence: 99%

cAMP-GEF cytoprotection by Src tyrosine kinase activation of phosphoinositide-3-kinase p110 β/α in rat hepatocytes

Gates¹,

Hohenester²,

Anwer³

et al. 2009

American Journal of Physiology-Gastrointestinal and Liver Physi

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“…Endogenous mediators that promote Akt activation may therefore downregulate hepatocyte iNOS expression in vitro and in vivo (16,21) and limit iNOS-induced tissue injury in times of stress. Insulin had little effect on p38 in our experiments, and SB203580 had more potent effects on Akt than p38 in these cultures.…”

Section: Discussionmentioning

confidence: 99%

Insulin inhibits hepatocyte iNOS expression induced by cytokines by an Akt-dependent mechanism

Nweze

Smith

Zhang

2012

American Journal of Physiology-Gastrointestinal and Liver Physi

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Harbrecht BG, Nweze I, Smith JW, Zhang B. Insulin inhibits hepatocyte iNOS expression induced by cytokines by an Akt-dependent mechanism. Am J Physiol Gastrointest Liver Physiol 302: G116-G122, 2012. First published October 28, 2011 doi:10.1152/ajpgi.00114.2011.-Hepatocyte inducible nitric oxide synthese (iNOS) expression is a tightly controlled pathway that mediates hepatic inflammation and hepatocyte injury in a variety of disease states. We have shown that cyclic adenosine monophosphate (cAMP) regulates cytokine-induced hepatocyte iNOS expression through mechanisms that involve protein kinase B/Akt. We hypothesized that insulin, which activates Akt signaling in hepatocytes, as well as signaling through p38 and MAPK p42/p44, would regulate iNOS expression during inflammation. In primary rat hepatocytes, insulin inhibited cytokine-stimulated nitrite accumulation and iNOS expression in a dose-dependent manner. Inhibition of MAPK p42/p44 with PD98059 had no effect on iNOS activation, whereas SB203580 to block p38 reversed insulin's inhibitory effect. However, insulin did not increase p38 activation and inhibition of p38 signaling with a dominant negative p38 plasmid had no effect on cytokine-or insulin-mediated effects on iNOS. We found that SB203580 blocked insulin-induced Akt activation. Inhibition of Akt signaling with LY294002 or a dominant negative Akt plasmid increased cytokine-stimulated nitrite production and iNOS protein expression and blocked the inhibitory effects of insulin. NF-B induces iNOS expression and can be regulated by Akt, but insulin had no effect on cytokine-mediated IB␣ levels or NF-B p65 translocation. Our data demonstrate that insulin inhibits cytokine-stimulated hepatocyte iNOS expression and does so through effects on Aktmediated signaling. nitric oxide; nitric oxide synthase; sepsis; inflammation; liver HEPATIC DYSFUNCTION WAS IDENTIFIED decades ago as a component of the multiple organ failure syndrome (10). Liver dysfunction can be manifested in a variety of ways and is associated with increased morbidity and mortality in critically ill patients (13,18,25). Nitric oxide synthesis is an important pathway in the host's response to inflammation and mediates hepatic dysfunction and hepatic injury in models of shock and organ failure (19,28). Proinflammatory cytokines stimulate hepatic nitric oxide production, and we have shown that glucagon and cyclic AMP inhibit hepatocyte inducible nitric oxide synthase (iNOS) expression (14 -16). The role of other counterregulatory mediators produced in shock and sepsis on iNOS regulation remain incompletely studied (8). Glucagon and cAMP regulate hepatocyte iNOS expression through intracellular signaling pathways involving 20,44). Our laboratory and others have demonstrated that cAMP activates protein kinase B/Akt in hepatocytes (9,27,43,45). Akt-mediated signaling changes have profound effects on hepatocyte function and physiology (9, 27, 43), and we have shown that the cAMP-induced changes in iNOS expression are mediated in part through Akt-induce...

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Glucagon Regulates Hepatic Inducible Nitric Oxide Synthesis in Vivo

Cited by 19 publications

References 36 publications

Calcium-mediated signaling and calmodulin-dependent kinase regulate hepatocyte-inducible nitric oxide synthase expression

Calcium-mediated signaling and calmodulin-dependent kinase regulate hepatocyte-inducible nitric oxide synthase expression

cAMP-GEF cytoprotection by Src tyrosine kinase activation of phosphoinositide-3-kinase p110 β/α in rat hepatocytes

Insulin inhibits hepatocyte iNOS expression induced by cytokines by an Akt-dependent mechanism

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