Peroxisome-Generated Hydrogen Peroxide as Important Mediator of Lipotoxicity in Insulin-Producing Cells

Elsner, Matthias; Gehrmann, Wiebke; Lenzen, Sigurd

doi:10.2337/db09-1401

Cited by 195 publications

(168 citation statements)

References 48 publications

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“…ER stress and enhanced ROS production have been implicated in beta cell glucolipotoxicity [11,28,45], although others contest this theory [37]. The contribution made by beta cellgenerated 4-hydroxyalkenals to this process is unclear.…”

Section: Discussionmentioning

confidence: 99%

“…Beta cells respond to increased circulating levels of NEFA by augmenting the secretion of insulin, which facilitates their peripheral disposal [4][5][6][7]. Long-term exposure of beta cells to high levels of glucose and NEFA reduces this response in a phenomenon termed 'glucolipotoxicity', which is characterised by altered membrane fluidity, protein palmitoylation, generation of ceramides, mitochondrial dysfunction, endoplasmic reticulum (ER) stress, autophagy and apoptosis [8][9][10][11].…”

Section: Introductionmentioning

confidence: 99%

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Beta cell response to nutrient overload involves phospholipid remodelling and lipid peroxidation

et al. 2015

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Aims/hypothesis Membrane phospholipids are the major intracellular source for fatty acid-derived mediators, which regulate myriad cell functions. We showed previously that high glucose levels triggered the hydrolysis of polyunsaturated fatty acids from beta cell phospholipids. These fatty acids were subjected to free radical-catalysed peroxidation to generate the bioactive aldehyde 4-hydroxy-2E-nonenal (4-HNE). The latter activated the nuclear peroxisome proliferator-activated receptor-δ (PPARδ), which in turn augmented glucosestimulated insulin secretion. The present study aimed at investigating the combined effects of glucose and fatty acid overload on phospholipid turnover and the subsequent generation of lipid mediators, which affect insulin secretion and beta cell viability. Methods INS-1E cells were incubated with increasing glucose concentrations (5-25 mmol/l) without or with palmitic acid (PA; 50-500 μmol/l) and taken for fatty acid-based lipidomic analysis and functional assays. Rat isolated islets of Langerhans were used similarly. Results PA was incorporated into membrane phospholipids in a concentration-and time-dependent manner; incorporation was highest at 25 mmol/l glucose. This was coupled to a rapid exchange with saturated, mono-unsaturated and polyunsaturated fatty acids. Importantly, released arachidonic acid and linoleic acid were subjected to peroxidation, resulting in the generation of 4-HNE, which further augmented insulin secretion by activating PPARδ in beta cells. However, this adaptive increase in insulin secretion was abolished at high glucose and PA levels, which induced endoplasmic reticulum stress, apoptosis and cell death. Conclusions/interpretation These findings highlight a key role for phospholipid remodelling and fatty acid peroxidation in mediating adaptive and cytotoxic interactions induced by nutrient overload in beta cells.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Beta cell response to nutrient overload involves phospholipid remodelling and lipid peroxidation

et al. 2015

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“…Accumulating evidence indicates that lipotoxicity contributes to beta cell injury and plays a critical role in the development of type 2 diabetes [1][2][3]. NEFA is chemically classified into saturated and unsaturated fatty acids.…”

Section: Introductionmentioning

confidence: 99%

Elevated circulating stearic acid leads to a major lipotoxic effect on mouse pancreatic beta cells in hyperlipidaemia via a miR-34a-5p-mediated PERK/p53-dependent pathway

Hao

et al. 2016

Diabetologia

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Aims/hypothesis Serum stearic acid (C18:0) is elevated in individuals with hyperlipidaemia and type 2 diabetes. However, the lipotoxicity induced by increased stearic acid in beta cells has not been well described. This study aimed to examine the adverse effects of stearic acid on beta cells and the potential mechanisms through which these are mediated. Methods Three groups of C57BL/6 mice were fed a normal diet or a high-stearic-acid/high-palmitic-acid diet for 24 weeks, respectively. The microRNA (miR) profiles of islets were determined by microarray screening. Islet injury was detected with co-staining using the TUNEL assay and insulin labelling. A lentiviral vector expressing anti-miRNA-34a-5p oligonucleotide (AMO-34a-5p) was injected into mice via an intraductal pancreatic route. Results In both mouse islets and cultured rat insulinoma INS-1 cells, stearic acid exhibited a stronger lipotoxic role than other fatty acids, owing to repression of B cell CLL/ lymphoma 2 (BCL-2) and BCL-2-like 2 (BCL-W) by stearic acid stimulation of miR-34a-5p. The stearic-acid-induced lipotoxicity and reduction in insulin secretion were alleviated by AMO-34a-5p. Further investigations in INS-1 cells revealed that p53 was involved in stearic-acid-induced elevation of miR-34a-5p, owing in part to activation of protein kinaselike endoplasmic reticulum kinase (PERK). Conversely, silencing PERK alleviated stearic-acid-induced p53, miR-34a-5p and lipotoxicity. Conclusions/interpretation These findings provide new insight for understanding the molecular mechanisms underlying not only the deleterious impact of stearic-acid-induced lipotoxicity but also apoptosis in beta cells and progression to type 2 diabetes.

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“…Pancreatic islet b-cell apoptosis has been implicated in the pathogenesis of T2DM by causing absolute or relative insulin deficiencies (Elsner et al 2011). During the progression of T2DM, glucotoxicity is an important contributing factor for the progression of b-cell failure and the development of diabetic complications (Rhodes 2005).…”

Section: Discussionmentioning

confidence: 99%

“…Chronic high glucose, free fatty acids, and endoplasmic reticulum (ER) stress have been found to be toxic to pancreatic b-cells and impairing cellular functioning (Elsner et al 2011). However, the mechanisms underlying b-cell dysfunction and the resulting apoptosis via those factors have not been fully characterized (Donath et al 1999, Kim et al 2005, Lablanche et al 2011.…”

Section: Introductionmentioning

confidence: 99%

Involvement of the Ca2+-responsive transactivator in high glucose-induced β-cell apoptosis

Men

Peng²,

Wang³

et al. 2012

Journal of Endocrinology

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The calcium-regulated transcription coactivator, Ca 2C -responsive transactivator (CREST) was expressed in pancreatic b-cells. Moreover, CREST expression became significantly increased in pancreatic islets isolated from hyperglycemic Goto-Kakizaki rats compared with normoglycemic Wistar controls. In addition, culture of b-cells in the presence of high glucose concentrations also increased CREST expression in vitro. To further investigate the role of this transactivator in the regulation of b-cell function, we established a stable b-cell line with inducible CREST expression. Hence, CREST overexpression mimicked the glucotoxic effects on insulin secretion and cell growth in b-cells. Moreover, high glucose-induced apoptosis was aggravated by upregulation of the transactivator but inhibited when CREST expression was partially silenced by siRNA technology. Further investigation found that upregulation of Bax and downregulation of Bcl2 was indeed induced by its expression, especially under high glucose conditions. In addition, as two causing factors leading to b-cell apoptosis under diabetic conditions, endoplasmic reticulum stress and high free fatty acid, mimicked the high glucose effects on CREST upregulation and generation of apoptosis in b-cells, and these effects were specifically offset by the siRNA knockdown of CREST. These results indicated that CREST is implicated in b-cell apoptosis induced by culture in high glucose and hence that CREST may become a potential pharmacological target for the prevention and treatment of type 2 diabetes mellitus.

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Peroxisome-Generated Hydrogen Peroxide as Important Mediator of Lipotoxicity in Insulin-Producing Cells

Cited by 195 publications

References 48 publications

Beta cell response to nutrient overload involves phospholipid remodelling and lipid peroxidation

Beta cell response to nutrient overload involves phospholipid remodelling and lipid peroxidation

Elevated circulating stearic acid leads to a major lipotoxic effect on mouse pancreatic beta cells in hyperlipidaemia via a miR-34a-5p-mediated PERK/p53-dependent pathway

Involvement of the Ca2+-responsive transactivator in high glucose-induced β-cell apoptosis

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