PPARγ ligands induce ER stress in pancreatic β-cells: ER stress activation results in attenuation of cytokine signaling

Weber, Sarah M.; Chambers, Kari T.; Bensch, Kenneth G.; Scarim, Anna L.; Corbett, John A.

doi:10.1152/ajpendo.00331.2004

Cited by 64 publications

(76 citation statements)

References 46 publications

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“…Nitric oxide is known to cause ER stress and activation of the UPR in a number of cell types, including ␤-cells (12,38,53). Consistent with these previous studies, DEANO treatment of INS832/13 cells for 10 to 60 min results in increased phosphorylation of PERK and its substrate eIF2␣ (Fig.…”

Section: Nitricsupporting

confidence: 86%

IRE1-Dependent Activation of AMPK in Response to Nitric Oxide

Meares

Hughes

Naatz

et al. 2011

Molecular and Cellular Biology

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While there can be detrimental consequences of nitric oxide production at pathological concentrations, eukaryotic cells have evolved protective mechanisms to defend themselves against this damage. The unfoldedprotein response (UPR), activated by misfolded proteins and oxidative stress, is one adaptive mechanism that is employed to protect cells from stress. Nitric oxide is a potent activator of AMP-activated protein kinase (AMPK), and AMPK participates in the cellular defense against nitric oxide-mediated damage in pancreatic ␤-cells. In this study, the mechanism of AMPK activation by nitric oxide was explored. The known AMPK kinases LKB1, CaMKK, and TAK1 are not required for the activation of AMPK by nitric oxide. Instead, this activation is dependent on the endoplasmic reticulum (ER) stress-activated protein IRE1. Nitric oxide-induced AMPK phosphorylation and subsequent signaling to AMPK substrates, including Raptor, acetyl coenzyme A carboxylase, and PGC-1␣, is attenuated in IRE1␣-deficient cells. The endoribonuclease activity of IRE1 appears to be required for AMPK activation in response to nitric oxide. In addition to nitric oxide, stimulation of IRE1 endoribonuclease activity with the flavonol quercetin leads to IRE1-dependent AMPK activation. These findings indicate that the RNase activity of IRE1 participates in AMPK activation and subsequent signaling through multiple AMPK-dependent pathways in response to nitrosative stress.Nitric oxide, an important mediator of both physiological and pathological processes, has been implicated in the development of a number of inflammatory diseases. When produced at low concentrations, nitric oxide can promote cell growth and survival. At high concentrations, such as those produced during inflammation by inducible nitric oxide synthase (iNOS), nitric oxide induces extensive cellular injury that includes DNA damage, inhibition of oxidative metabolism, and induction of endoplasmic reticulum (ER) stress (5, 12, 39). Pancreatic ␤-cells are exquisitely sensitive to oxidative damage, as glucose-stimulated insulin secretion requires the oxidation of glucose to CO 2 , resulting in the accumulation of ATP. Nitric oxide, produced in micromolar concentrations in response to interleukin 1 (IL-1) and gamma interferon (IFN-␥), mediates the damaging effects of these cytokines on ␤-cell function (3, 33). While nitric oxide stimulates cellular damage, it also activates a number of signaling pathways that limit additional cellular damage and repair existing damage. In pancreatic ␤-cells, the protective responses activated by nitric oxide include (i) JNK-dependent induction of GADD45␣ (growth arrest and DNA damage-inducible protein 45␣) and DNA repair, (ii) activation of AMP-activated protein kinase (AMPK), resulting in enhanced metabolic recovery, and (iii) activation of the unfolded-protein response (UPR) (25,34,38,54,57,61).AMPK is a conserved heterotrimeric (␣, ␤, and ␥ subunits) serine/threonine kinase involved in sensing and responding to the energetic demand within eukaryotic cel...

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Section: Nitricsupporting

confidence: 86%

IRE1-Dependent Activation of AMPK in Response to Nitric Oxide

Meares

Hughes

Naatz

et al. 2011

Molecular and Cellular Biology

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“…A paradoxical effect of proteasome inhibition has also been reported (20) in rat vascular smooth muscle. These findings also raise the question of whether the basic mechanisms regulating the expression and degradation of iNOS might be circumvented by the lack of appropriate signaling due to the mere presence of a proteasome inhibitor or by other hitherto less known mechanisms possibly related to endoplasmic reticulum stress (47).…”

Section: Discussionmentioning

confidence: 99%

Expression of islet inducible nitric oxide synthase and inhibition of glucose-stimulated insulin release after long-term lipid infusion in the rat is counteracted by PACAP27

Qader

Jimenez-Feltström²,

Ekelund³

et al. 2007

American Journal of Physiology-Endocrinology and Metabolism

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Qader SS, Jimenez-Feltström J, Ekelund M, Lundquist I, Salehi A. Expression of islet inducible nitric oxide synthase and inhibition of glucose-stimulated insulin release after long-term lipid infusion in the rat is counteracted by PACAP27. Am J Physiol Endocrinol Metab 292: E1447-E1455, 2007. First published January 30, 2007; doi:10.1152/ajpendo.00172.2006.-Chronic exposure of pancreatic islets to elevated plasma lipids (lipotoxicity) can lead to ␤-cell dysfunction, with overtime becoming irreversible. We examined, by confocal microscopy and biochemistry, whether the expression of islet inducible nitric oxide synthase (iNOS) and the concomitant inhibition of glucose-stimulated insulin release seen after lipid infusion in rats was modulated by the islet neuropeptide pituitary adenylate cyclase-activating polypeptide (PACAP)27. Lipid infusion for 8 days induced a strong expression of islet iNOS, which was mainly confined to ␤-cells and was still evident after incubating islets at 8.3 mmol/l glucose. This was accompanied by a high iNOS-derived NO generation, a decreased insulin release, and increased cyclic GMP accumulation. No iNOS expression was found in control islets. Addition of PACAP27 to incubated islets from lipid-infused rats resulted in loss of iNOS protein expression, increased cyclic AMP, decreased cyclic GMP, and suppression of the activities of neuronal constitutive (nc)NOS and iNOS and increased glucose-stimulated insulin response. These effects were reversed by the PKA inhibitor H-89. The suppression of islet iNOS expression induced by PACAP27 was not affected by the proteasome inhibitor MG-132, which by itself induced the loss of iNOS protein, making a direct proteasomal involvement less likely. Our results suggest that PACAP27 through its cyclic AMP-and PKA-stimulating capacity strongly suppresses not only ncNOS but, importantly, also the lipid-induced stimulation of iNOS expression, possibly by a nonproteasomal mechanism. Thus PACAP27 restores the impairment of glucose-stimulated insulin release and additionally might induce cytoprotection against deleterious actions of iNOS-derived NO in ␤-cells. pancreatic islets; insulin secretion; isoforms of nitric oxide synthase; pituitary adenylate cyclase-activating polypeptide 27 THE SOLUTION USED for total parenteral nutrition (TPN) contains a high amount of lipids, which results in increased plasma levels of free fatty acid (FFA), triglycerides, and cholesterol (8,31,34,36). FFA has complex effects on pancreatic ␤-cells and insulin secretion (8,9,25,31,32,34,36,45,51). Hence, FFA acutely stimulates insulin secretion from isolated pancreatic islets (9), whereas long-term incubation (24 h) of islets in the presence of FFAs negatively modulates ␤-cell function and results in a markedly decreased glucose-stimulated release of insulin (51). Indeed, it has been known for a long time that chronic elevation of plasma FFA impairs the insulin-secreting response to glucose in both humans and animals (8,31,32,34,36,45,51), and this hyperlipidemia has been suggest...

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“…ER stress might produce signals mediating glucose-induced impairment of function and death (55)(56)(57). However, activation of the unfolded protein response in ␤-cells in response to ER stress may also provide protection to ␤-cells by attenuating the ability of cytokines such as IL-1␤ to signal and activate the expression of downstream targets (58). ER stress has recently been observed in obesity and linked to insulin resistance (59).…”

Section: Insulin Receptor Substrate 2 Nuclear Factor-b Endoplasmic mentioning

confidence: 99%

Mechanisms of β-Cell Death in Type 2 Diabetes

et al. 2005

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A decrease in the number of functional insulin-producing ␤-cells contributes to the pathophysiology of type 2 diabetes. Opinions diverge regarding the relative contribution of a decrease in ␤-cell mass versus an intrinsic defect in the secretory machinery. Here we review the evidence that glucose, dyslipidemia, cytokines, leptin, autoimmunity, and some sulfonylureas may contribute to the maladaptation of ␤-cells. With respect to these causal factors, we focus on Fas, the ATP-sensitive K ؉ channel, insulin receptor substrate 2, oxidative stress, nuclear factor-B, endoplasmic reticulum stress, and mitochondrial dysfunction as their respective mechanisms of action. Interestingly, most of these factors are involved in inflammatory processes in addition to playing a role in both the regulation of ␤-cell secretory function and cell turnover. Thus, the mechanisms regulating ␤-cell proliferation, apoptosis, and function are inseparable processes. Diabetes 54 (Suppl. 2):S108 -S113, 2005 F or many years, the contribution of a reduction in ␤-cell mass to the development of type 2 diabetes was heavily debated. Recently, several publications have convincingly confirmed this hypothesis (1-3), leading to a rapid overemphasis of this etiological factor. Indeed, other mechanisms contributing to the failure of the ␤-cell to produce enough insulin appear more and more neglected. While we strongly believe that ␤-cell destruction is an important etiological factor in the development and progression of type 2 diabetes, in this review, we will highlight evidence that this is not dissociable from an intrinsic secretory defect. We will show that pathways regulating ␤-cell turnover are also implicated in ␤-cell insulin secretory function. It follows that adaptive mechanisms of function and mass share common regulatory pathways and will therefore act in concert. Depending on the prevailing concentration and the intracellular pathways activated, some factors may be deleterious to ␤-cell mass while enhancing insulin secretion, protective to the ␤-cell while inhibiting function, or even protective to the ␤-cell while enhancing function. It will become apparent that the failure of the ␤-cell in type 2 diabetes is akin to a multifactorial equation, with an overall negative result.Thus, although we will review the factors and mechanisms regulating ␤-cell mass individually, only in a minority of diabetic patients does one single etiological factor underlie the failure of the ␤-cell. In addition to maturityonset diabetes of the young, another example of this is autoimmune-mediated destruction of ␤-cells in young lean individuals. However, given that the incidence of type 1 diabetes increases with obesity (4), that insulin resistance is a risk factor for the progression of this condition (5), and that ϳ50% of the general population carry the same genetic predisposition (6), this example already implicates multiple etiological factors. Recognition of ␤-cell destruction not only in type 1 but also in type 2 diabetes led us to recently propose a unif...

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PPARγ ligands induce ER stress in pancreatic β-cells: ER stress activation results in attenuation of cytokine signaling

Abstract: . PPAR␥ ligands induce ER stress in pancreatic ␤-cells: ER stress activation results in attenuation of cytokine signaling.

Cited by 64 publications

References 46 publications

IRE1-Dependent Activation of AMPK in Response to Nitric Oxide

IRE1-Dependent Activation of AMPK in Response to Nitric Oxide

Expression of islet inducible nitric oxide synthase and inhibition of glucose-stimulated insulin release after long-term lipid infusion in the rat is counteracted by PACAP27

Mechanisms of β-Cell Death in Type 2 Diabetes

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