Mechanisms involved in the cytotoxic and cytoprotective actions of saturated versus monounsaturated long-chain fatty acids in pancreatic β-cells

Diakogiannaki, Eleftheria; Dhayal, Shalinee; Childs, Caroline E.; Calder, Philip C.; Welters, Hannah J.; Morgan, Noel G.

doi:10.1677/joe-07-0082

Cited by 77 publications

(87 citation statements)

References 46 publications

(71 reference statements)

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“…Other studies corroborate the favorable effects of palmitoleic acid on insulin action (71,107,108) through translocation of glucose transporter 4 (GLUT-4) to the plasma membrane (109). Cellular studies found that palmitoleate induces b cell proliferation and secretory function (110,111), regulates the expression and degradation of metabolic enzymes (16), and prevents endoplasmatic reticulum stress and apoptosis mediated by palmitate (65,72). Thus, endogenously produced or dietary palmitoleate has been related to a reduced onset of diabetes; therefore, it could be a potential strategy for preventing this disease in humans.…”

Section: Diabetes and Insulin Resistancementioning

confidence: 71%

The Role of the Novel Lipokine Palmitoleic Acid in Health and Disease

Frigolet

Gutiérrez-Aguilar

2017

Advances in Nutrition

183

143

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The monounsaturated fatty acid palmitoleate (palmitoleic acid) is one of the most abundant fatty acids in serum and tissues, particularly adipose tissue and liver. Its endogenous production by stearoyl-CoA desaturase 1 gives rise to its cis isoform, cis-palmitoleate. Although trans-palmitoleate is also synthesized in humans, it is mainly found as an exogenous source in ruminant fat and dairy products. Recently, palmitoleate was considered to be a lipokine based on evidence demonstrating its release from adipose tissue and its metabolic effects on distant organs. After this finding, research has been performed to determine whether palmitoleate has beneficial effects on metabolism and to elucidate the underlying mechanisms. Thus, the aim of this work was to review the current status of knowledge about palmitoleate, its metabolism, and its influence on metabolic abnormalities. Results have shown mixed cardiovascular effects, direct or inverse correlations with obesity, and hepatosteatosis, but a significant amelioration or prevention of insulin resistance and diabetes. Finally, the induction of palmitoleate release from adipose tissue, dietary intake, and its supplementation are all interventions with a potential impact on certain metabolic diseases. Adv Nutr 2017;8(Suppl):173S-81S.

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Section: Diabetes and Insulin Resistancementioning

confidence: 71%

The Role of the Novel Lipokine Palmitoleic Acid in Health and Disease

Frigolet

Gutiérrez-Aguilar

2017

Advances in Nutrition

183

143

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“…Among such mechanisms, tripalmitin formation has been proposed (Moffitt et al 2005). Esterification of the fatty acid may not necessarily be b-cell toxic, however (Diakogiannaki et al 2007).…”

Section: Discussionmentioning

confidence: 99%

Diazoxide-induced β-cell rest reduces endoplasmic reticulum stress in lipotoxic β-cells

Sargsyan¹,

Ortsäter

Thörn³

et al. 2008

Journal of Endocrinology

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Elevated levels of glucose and lipids are characteristics of individuals with type 2 diabetes mellitus (T2DM). The enhanced nutrient levels have been connected with deterioration of b-cell function and impaired insulin secretion observed in these individuals. A strategy to improve b-cell function in individuals with T2DM has been intermittent administration of K ATP channel openers. After such treatment, both the magnitude and kinetics of insulin secretion are markedly improved. In an attempt to further delineate mechanisms of how openers of K ATP channels improve b-cell function, the effects of diazoxide on markers of endoplasmic reticulum (ER) stress was determined in b-cells exposed to the fatty acid palmitate. The eukaryotic translation factor 2-alpha kinase 3 (EIF2AK3; also known as PERK) and endoplasmic reticulum to nucleus signaling 1 (ERN1; also known as IRE1) pathways, but not the activating transcription factor (ATF6) pathway of the unfolded protein response, are activated in such lipotoxic b-cells. Inclusion of diazoxide during culture attenuated activation of the EIF2AK3 pathway but not the ERN1 pathway. This attenuation was associated with reduced levels of DNA-damage inducible transcript 3 (DDIT3; also known as CHOP) and b-cell apoptosis was decreased. It is concluded that reduction of ER stress may be a mechanism by which diazoxide improves b-cell function.

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“…In previous studies, we have shown that treatment of BRIN-BD11 cells with palmitate leads to an increase in cell death mediated by apoptosis and that this response is attenuated when palmitoleate is included in the incubation medium (Welters et al 2004, Diakogiannaki et al 2007. In confirmation of these observations, it was observed in the present work that exposure of the cells to 250 mM palmitate for 18 h in the presence of BSA but no serum, resulted in a large loss of viability (control: 77G3% live cells; palmitate: 21G2%; P!0 .…”

Section: Electron Microscopic Analysis Of Brin-bd11 Cells Following Tmentioning

confidence: 99%

“…This concept is important since it has emerged that b-cell lipotoxicity results from the activation of specific proapoptotic pathways that are differentially regulated by saturated and monounsaturated molecules. Thus, while long-chain saturated fatty acids such as palmitate (C16:0) and stearate (C18:0) are powerfully lipotoxic to pancreatic b-cells, the equivalent monounsaturated molecules (palmitoleate (C16:1) and oleate (C18:1)) are potently cytoprotective under in vitro conditions (Welters et al 2004, Diakogiannaki et al 2007, Dhayal et al 2008. In the present work, we have investigated the possibility that this may reflect a differential activation of the integrated stress response by saturated and monounsaturated fatty acids.…”

Section: Introductionmentioning

confidence: 99%

Differential regulation of the endoplasmic reticulum stress response in pancreatic β-cells exposed to long-chain saturated and monounsaturated fatty acids

Diakogiannaki

Welters²,

Morgan³

2008

Journal of Endocrinology

Self Cite

110

112

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Exposure of pancreatic b-cells to long-chain fatty acids leads to the activation of some components of the endoplasmic reticulum (ER) stress pathway and this mechanism may underlie the ability of certain fatty acids to promote b-cell death. We have studied ER stress in BRIN-BD11 b-cells exposed to either the saturated fatty acid palmitate (C16:0) or the monounsaturated palmitoleate (C16:1). Palmitate (0 . 025-0 . 25 mM) induced the expression of various markers of the RNA-dependent protein kinase-like ER eukaryotic initiation factor 2a (eIF2a) kinase (PERK)-dependent pathway of ER stress (phospho-eIF2a; ATF4, activating transcription factor 4 and C/EBP homologous protein (CHOP-10)) although it failed to promote the expression of the ER chaperone GRP78. By contrast, palmitoleate did not induce any markers of the ER stress pathway even at concentrations as high as 1 mM. When palmitate and palmitoleate were added in combination, a marked attenuation of the ER stress response occurred. Under these conditions, the levels of phospho-eIF2a, ATF4 and CHOP-10 were reduced to less than those found in control cells. Palmitoleate also attenuated the ER stress response to the protein glycosylation inhibitor, tunicamycin, and improved the viability of the cells exposed to this agent. Exposure of the BRIN-BD11 cells to the protein phosphatase inhibitor, salubrinal, in the absence of fatty acids resulted in increased eIF2a phosphorylation but this was abolished by co-incubation with palmitoleate. We conclude that saturated fatty acids activate components of the PERK-dependent ER stress pathway in b-cells, ultimately leading to increased apoptosis. This effect is antagonised by monounsaturates that may exert their anti-apoptotic actions by regulating the activity of one or more kinase enzymes involved in mediating the phosphorylation of eIF2a.

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Mechanisms involved in the cytotoxic and cytoprotective actions of saturated versus monounsaturated long-chain fatty acids in pancreatic β-cells

Cited by 77 publications

References 46 publications

The Role of the Novel Lipokine Palmitoleic Acid in Health and Disease

The Role of the Novel Lipokine Palmitoleic Acid in Health and Disease

Diazoxide-induced β-cell rest reduces endoplasmic reticulum stress in lipotoxic β-cells

Differential regulation of the endoplasmic reticulum stress response in pancreatic β-cells exposed to long-chain saturated and monounsaturated fatty acids

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