Comparison of the effect of individual saturated and unsaturated fatty acids on cell growth and death induction in the human pancreatic β-cell line NES2Y

Fürstova, V.; Kopska, Tereza; James, R. F. L.; Kovář, Jan

doi:10.1016/j.lfs.2007.12.023

Cited by 30 publications

(73 citation statements)

References 39 publications

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“…Interestingly, caspase-2-deficient mice display reduced body fat content, when compared with agematched wild-type mice [36], while diet-induced obese rats on dietary L-arginine supplementation gain much less white fat, concomitantly with reduced mRNA levels of caspase-2 [37]. In turn, TNF-α was shown to activate caspase-2, but not caspases-3 and -8, and also to induce apoptosis in HepG2 cells [38], while human pancreatic beta cell death induced by saturated fatty acids was also related to increased caspase-2 activity but not to caspase-3 [39]. It is likely that caspase-2 activation affects the metabolic syndrome and apoptosis during NAFLD.…”

Section: Discussionmentioning

confidence: 98%

Apoptosis and insulin resistance in liver and peripheral tissues of morbidly obese patients is associated with different stages of non-alcoholic fatty liver disease

et al. 2011

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Aims/hypothesis Non-alcoholic fatty liver disease (NAFLD) is associated with insulin resistance and characterised by different degrees of hepatic lesion. Its pathogenesis and correlation with apoptosis and insulin resistance in insulin target tissues remains incompletely understood. We investigated how insulin signalling, caspase activation and apoptosis correlate with different NAFLD stages in liver, muscle and visceral adipose tissues. Methods Liver, muscle and adipose tissue biopsies from 26 morbidly obese patients undergoing bariatric surgery were grouped according to the Kleiner-Brunt scoring system into simple steatosis, and less severe and more severe nonalcoholic steatohepatitis (NASH). Apoptosis was assessed by DNA fragmentation, and caspase-2 and -3 activation. Insulin signalling and c-Jun NH 2 -terminal kinase (JNK) proteins were evaluated by western blot. Results Caspase-3 and -2 activation, and DNA fragmentation were markedly increased in the liver of patients with severe NASH vs in that of those with simple steatosis (p<0.01). Muscle tissue, and to a lesser extent the liver, had decreased tyrosine phosphorylated insulin receptor and insulin receptor substrate in patients with severe NASH, compared with those with simple steatosis (p < 0.01 muscle; p < 0.05 liver). Concomitantly, Akt phosphorylation decreased in muscle, liver and visceral adipose tissues in patients with severe NASH (at least p< 0.05). Finally, JNK phosphorylation was significantly increased in muscle (p< 0.01) and liver (p<0.05) from NASH patients, compared with tissue from those with simple steatosis. Conclusions/interpretation Our results demonstrate a link between apoptosis, insulin resistance and different NAFLD stages, where JNK and caspase-2 may play a key regulatory role.

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Section: Discussionmentioning

confidence: 98%

Apoptosis and insulin resistance in liver and peripheral tissues of morbidly obese patients is associated with different stages of non-alcoholic fatty liver disease

et al. 2011

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“…The human pancreatic β-cell line NES2Y [21,26] was used. NES2Y are proliferating insulin-secreting cells with a defect in glucose responsiveness.…”

Section: Methodsmentioning

confidence: 99%

“…In our previous research we have newly demonstrated that caspase-2 is activated together with ER stress induction when apoptosis is induced by saturated fatty acids in human pancreatic β-cell line NES2Y [8,21]. There are also several other lines of evidence pointing at caspase-2 as a possible transducer of pro-apoptotic ER stress signaling in various cell types [22,23,24,25] although the mode of its activation under ER stress conditions is rather speculative.…”

Section: Introductionmentioning

confidence: 99%

Caspase-2 and JNK Activated by Saturated Fatty Acids are Not Involved in Apoptosis Induction but Modulate ER Stress in Human Pancreatic �-cells

Němcová‐Fürstová

Balušíková²,

Šrámek

et al. 2013

Cell Physiol Biochem

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Background: Fatty acid-induced apoptosis and ER stress of pancreatic β-cells contribute to the development of type 2 diabetes, however, the molecular mechanisms involved are unclear. Aims: In this study we have tested the role of caspase-2 and suggested ER stress mediator JNK in saturated fatty acid-induced apoptosis of the human pancreatic β-cells NES2Y. Results: We found that stearic acid at apoptosis-inducing concentration activated ER stress signaling pathways, i.e. IRE1α, PERK and ATF6 pathways, in NES2Y cells. During stearic acid-induced apoptosis, JNK inhibition did not decrease the rate of apoptosis nor the activation of caspase-8, -9, -7 and -2 and PARP cleavage. In addition, inhibition of JNK activity did not affect CHOP expression although it did decrease the induction of BiP expression after stearic acid treatment. Caspase-2 silencing had no effect on PARP as well as caspase-8, -9 and -7 cleavage and the induction of CHOP expression, however, it also decreased the induction of BiP expression. Surprisingly, caspase-2 silencing was accompanied by increased phosphorylation of c-Jun. Conclusions: We have demonstrated that caspase-2 as well as JNK are not key players in apoptosis induction by saturated fatty acids in human pancreatic β-cells NES2Y. However, they appear to be involved in the modulation of saturated fatty acid-induced ER stress signaling, probably by a mechanism independent of c-Jun phosphorylation.

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“…The monounsaturated fat oleate has been shown to affect ␤-cells in a number of studies, although it is generally considered to be less toxic (12,15,20,27,37,38). Oleate is thought to activate GPR40 in ␤-cells (19,54).…”

Section: Effects Of Palmitate On Er Stress and Cell Death Sustained mentioning

confidence: 99%

“…Chronic elevation of the long-chain saturated fatty acid palmitate has been shown to cause ␤-cell death (27,36,37,48,56). In contrast, unsaturated fatty acids such as oleate are considered to be less cytotoxic and in some cases protective against palmitate toxicity (20,27,37,38). Acute administration of palmitate is thought to cause a modest increase in insulin secretion (9,24), while prolonged exposure to this fatty acid increases basal insulin secretion while decreasing the relative response to glucose (66).…”

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confidence: 99%

Effects of palmitate on ER and cytosolic Ca²⁺homeostasis in β-cells

Gwiazda¹,

Yang²,

Lin³

et al. 2009

American Journal of Physiology-Endocrinology and Metabolism

179

158

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There are strong links between obesity, elevated free fatty acids, and type 2 diabetes. Specifically, the saturated fatty acid palmitate has pleiotropic effects on β-cell function and survival. In the present study, we sought to determine the mechanism by which palmitate affects intracellular Ca2+, and in particular the role of the endoplasmic reticulum (ER). In human β-cells and MIN6 cells, palmitate rapidly increased cytosolic Ca2+ through a combination of Ca2+ store release and extracellular Ca2+ influx. Palmitate caused a reversible lowering of ER Ca2+, measured directly with the fluorescent protein-based ER Ca2+ sensor D1ER. Using another genetically encoded indicator, we observed long-lasting oscillations of cytosolic Ca2+ in palmitate-treated cells. In keeping with this observed ER Ca2+ depletion, palmitate induced rapid phosphorylation of the ER Ca2+ sensor protein kinase R-like ER kinase (PERK) and subsequently ER stress and β-cell death. We detected little palmitate-induced insulin secretion, suggesting that these Ca2+ signals are poorly coupled to exocytosis. In summary, we have characterized Ca2+-dependent mechanisms involved in altered β-cell function and survival induced by the free fatty acid palmitate. We present the first direct evidence that free fatty acids reduce ER Ca2+ and shed light on pathways involved in lipotoxicity and the pathogenesis of type 2 diabetes.

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Comparison of the effect of individual saturated and unsaturated fatty acids on cell growth and death induction in the human pancreatic β-cell line NES2Y

Cited by 30 publications

References 39 publications

Apoptosis and insulin resistance in liver and peripheral tissues of morbidly obese patients is associated with different stages of non-alcoholic fatty liver disease

Apoptosis and insulin resistance in liver and peripheral tissues of morbidly obese patients is associated with different stages of non-alcoholic fatty liver disease

Caspase-2 and JNK Activated by Saturated Fatty Acids are Not Involved in Apoptosis Induction but Modulate ER Stress in Human Pancreatic �-cells

Effects of palmitate on ER and cytosolic Ca²⁺homeostasis in β-cells

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Comparison of the effect of individual saturated and unsaturated fatty acids on cell growth and death induction in the human pancreatic β-cell line NES2Y

Cited by 30 publications

References 39 publications

Apoptosis and insulin resistance in liver and peripheral tissues of morbidly obese patients is associated with different stages of non-alcoholic fatty liver disease

Apoptosis and insulin resistance in liver and peripheral tissues of morbidly obese patients is associated with different stages of non-alcoholic fatty liver disease

Caspase-2 and JNK Activated by Saturated Fatty Acids are Not Involved in Apoptosis Induction but Modulate ER Stress in Human Pancreatic �-cells

Effects of palmitate on ER and cytosolic Ca2+homeostasis in β-cells

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Effects of palmitate on ER and cytosolic Ca²⁺homeostasis in β-cells