Persistent activation of Akt or ERK prevents the toxicity induced by saturated and polyunsaturated fatty acids in RINm5F β-cells

Simon, Monique Nouailhetas; Azevedo-Martins, Anna Karenina; Amanso, Angélica M.; Carvalho, Carla Roberta de Oliveira; Curi, Rui

doi:10.1016/j.tiv.2008.02.012

Cited by 15 publications

(19 citation statements)

References 31 publications

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“…In study with RINm5F cells (rat pancreatic cell lineage), treatment for 4 h with PA induced a persistent activation of ERK. However, after this period the PA toxic effect was characterized by activation of PKC-d, therefore, over-riding any cell survival attempt (Simon et al, 2008).…”

Section: Journal Of Cellular Physiologymentioning

confidence: 99%

Activation of survival and apoptotic signaling pathways in lymphocytes exposed to palmitic acid

Takahashi

Cambiaghi

Luchessi

et al. 2011

Journal Cellular Physiology

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The toxicity of palmitic acid (PA) towards a human T-lymphocyte cell line (Jurkat) has been previously investigated but the mechanism(s) of PA action were unknown. In the current study, Jurkat cells were treated with sub-lethal concentrations of PA (50-150µM) and the activity of various signaling proteins was investigated. PA-induced apoptosis and mitochondrial dysfunction in a dose-dependent manner as evaluated by DNA fragmentation assay and depolarization of the mitochondrial membrane, respectively. PA treatment provoked release of cytochrome c from the inner mitochondrial membrane to the cytosol, activated members of the MAPK protein family JNK, p38, ERK, activated caspases 3/9, and increased oxidative/nitrosative stress. Exposure of cells to PA for 12 h increased insulin receptor (IR) and GLUT-4 levels in the plasma membrane. Insulin treatment (10 mU/ml/30 min) increased the phosphorylation of the IR β-subunit and Akt. A correlation was found between DNA fragmentation and expression levels of both IR and GLUT-4. Similar results were obtained for PA-treated lymphocytes from healthy human donors and from mesenteric lymph nodes of 48-h starved rats. PA stimulated glucose uptake by Jurkat cells (in the absence of insulin), stimulated accumulation of neutral lipids (triglyceride), and other lipid classes (phospholipids and cholesterol ester) but reduced glucose oxidation. Our results suggest that parameters of insulin signaling and non-oxidative glucose metabolism are stimulated as part of a coordinated response to prompt survival in lymphocytes exposed to PA but at higher concentrations, apoptosis prevails. These findings may explain aspects of lymphocyte dysfunction associated with diabetes.

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Section: Journal Of Cellular Physiologymentioning

confidence: 99%

Activation of survival and apoptotic signaling pathways in lymphocytes exposed to palmitic acid

Takahashi

Cambiaghi

Luchessi

et al. 2011

Journal Cellular Physiology

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“…It has been demonstrated that the ERK pathway can mediate both pro-apoptotic as well as anti-apoptotic signaling [ 23 , 24 , 25 , 26 ]. Regulation of ERK1/2 activation by saturated FAs in pancreatic β-cells has also been shown [ 27 , 28 ].…”

Section: Introductionmentioning

confidence: 99%

p38 MAPK Is Activated but Does Not Play a Key Role during Apoptosis Induction by Saturated Fatty Acid in Human Pancreatic β-Cells

Šrámek

Němcová‐Fürstová

Balušíková

et al. 2016

IJMS

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Saturated stearic acid (SA) induces apoptosis in the human pancreatic β-cells NES2Y. However, the molecular mechanisms involved are unclear. We showed that apoptosis-inducing concentrations of SA activate the p38 MAPK signaling pathway in these cells. Therefore, we tested the role of p38 MAPK signaling pathway activation in apoptosis induction by SA in NES2Y cells. Crosstalk between p38 MAPK pathway activation and accompanying ERK pathway inhibition after SA application was also tested. The inhibition of p38 MAPK expression by siRNA silencing resulted in a decrease in MAPKAPK-2 activation after SA application, but it had no significant effect on cell viability or the level of phosphorylated ERK pathway members. The inhibition of p38 MAPK activity by the specific inhibitor SB202190 resulted in inhibition of MAPKAPK-2 activation and noticeable activation of ERK pathway members after SA treatment but in no significant effect on cell viability. p38 MAPK overexpression by plasmid transfection produced an increase in MAPKAPK-2 activation after SA exposure but no significant influence on cell viability or ERK pathway activation. The activation of p38 MAPK by the specific activator anisomycin resulted in significant activation of MAPKAPK-2. Concerning the effect on cell viability, application of the activator led to apoptosis induction similar to application of SA (PARP cleavage and caspase-7, -8, and -9 activation) and in inhibition of ERK pathway members. We demonstrated that apoptosis-inducing concentrations of SA activate the p38 MAPK signaling pathway and that this activation could be involved in apoptosis induction by SA in the human pancreatic β-cells NES2Y. However, this involvement does not seem to play a key role. Crosstalk between p38 MAPK pathway activation and ERK pathway inhibition in NES2Y cells seems likely. Thus, the ERK pathway inhibition by p38 MAPK activation does not also seem to be essential for SA-induced apoptosis.

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“…These findings support the proposition that short-time exposure to palmitic acid raises pancreatic A cell survival. Simon et al 24 have shown that short-period exposure to fatty acids is not enough to induce cytotoxicity in pancreatic A cells because survival pathways are activated. Therefore, palmitate is an important modulator of pancreatic islet function.…”

Section: Discussionmentioning

confidence: 99%

Palmitate Activates Insulin Signaling Pathway in Pancreatic Rat Islets

et al. 2009

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Objective: To investigate the action of palmitate on insulin receptor (IR) signaling pathway in rat pancreatic islets. The following proteins were studied: IR substrate-1 and -2 (IRS1 and IRS2), phosphatidylinositol 3-kinase, extracellular signalYregulated protein kinase-1 and -2 (ERK1/2), and signal transducer and activator of transcription 3 (STAT3). Results: The exposure of rat pancreatic islets to 0.1-mmol/L palmitate for up to 30 minutes produced a significant increase of Tyr phosphorylation in IRS2 but not in IRS1. The association of phosphatidylinositol 3-kinase with IRS2 was also upregulated by palmitate. Exposure to 5.6-mmol/L glucose caused a gradual decrease in ERK1/2 (Thr202/ Tyr204) and STAT3 (serine [Ser727]) phosphorylations after 30-minute incubation. The addition of palmitate (0.1 mmol/L), associated with 5.6-mmol/L glucose, abolished these latter effects of glucose after 15-minute incubation.Conclusions: Palmitate at physiological concentration associated with 5.6-mmol/L glucose activates IR signaling pathway in pancreatic A cells.Key Words: pancreatic islets, palmitate, insulin receptor signaling, IRS2, ERK1/2, STAT3 (Pancreas 2009;38: 578Y584) S hort-term exposure (1 hour) of pancreatic islets to free fatty acids (FFAs) increases glucose-stimulated insulin secretion (GSIS) at high glucose concentration (16.7 mmol/L). 1Y3 However, islet exposure to palmitate for a prolonged period (24 hours) shows low GSIS. 4,5 The potentiation of GSIS is associated with inhibition of FFA oxidation, increased FFA esterification, and complex lipid synthesis by pancreatic A cells. 6 Pancreatic islets convert glucose into fatty acids, and a substantial amount of them is released to extracellular medium after 60-minute static incubation. 7 The exported FFAs probably have an important paracrine function, amplifying GSIS. Despite this, the precise mechanisms by which FFA modulate insulin release by pancreatic A cell are not fully understood yet.Evidence exists that the autocrine action of insulin through insulin/insulin

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Persistent activation of Akt or ERK prevents the toxicity induced by saturated and polyunsaturated fatty acids in RINm5F β-cells

Cited by 15 publications

References 31 publications

Activation of survival and apoptotic signaling pathways in lymphocytes exposed to palmitic acid

Activation of survival and apoptotic signaling pathways in lymphocytes exposed to palmitic acid

p38 MAPK Is Activated but Does Not Play a Key Role during Apoptosis Induction by Saturated Fatty Acid in Human Pancreatic β-Cells

Palmitate Activates Insulin Signaling Pathway in Pancreatic Rat Islets

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