Diminished Acyl-CoA Synthetase Isoform 4 Activity in INS 832/13 Cells Reduces Cellular Epoxyeicosatrienoic Acid Levels and Results in Impaired Glucose-stimulated Insulin Secretion

Klett, Eric L.; Chen, Shufen; Edin, Matthew L.; Li, Lei O.; Ilkayeva, Olga; Zeldin, Darryl C.; Newgard, Christopher B.; Coleman, Rosalind A.

doi:10.1074/jbc.m113.481077

Cited by 56 publications

(45 citation statements)

References 48 publications

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“…Falck et al reported that 5,6-EET doubled insulin release from isolated rat pancreatic islets, compared with control values. [25] In contrast, Klett et al have reported that unesterified EETs decrease glucose-stimulated insulin secretion in isolated islets,[26] and we have found that glucosestimulated insulin secretion is increased in Cyp2c44 null mice, the equivalent of CYP2C8/9 in humans (unpublished data). In the current study, we do not find any relationship between either EPHX2 genotype or EETs and glucose-stimulated insulin secretion in humans.…”

Section: Discussionmentioning

confidence: 55%

Arg287Gln variant of EPHX2 and epoxyeicosatrienoic acids are associated with insulin sensitivity in humans

Ramirez

Shuey

Milne

et al. 2014

Prostaglandins & Other Lipid Mediators

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Epoxyeicosatrienoic acids (EETs) protect against the development of insulin resistance in rodents. EETs are hydrolyzed to less biologically active diols by soluble epoxide hydrolase (encoded for by EPHX2). Functional variants of EPHX2 encode for enzymes with increased (Lys55Arg) or decreased (Arg287Gln) hydrolase activity. This study tested the hypothesis that variants of EPHX2 are associated with insulin sensitivity or secretion in humans. Subjects participating in metabolic phenotyping studies were genotyped. Eighty-five subjects underwent hyperglycemic clamps. There was no relationship between the Lys55Arg genotype and insulin sensitivity or secretion. In contrast, the EPHX2 287Gln variant was associated with higher insulin sensitivity index (p=0.019 controlling for body mass index and metabolic syndrome). Also, there was an interactive effect of EPHX2 Arg287Gln genotype and body mass index on insulin sensitivity index (p=0.029). There was no relationship between EPHX2 Arg287Gln genotype and acute or late-phase glucose-stimulated insulin secretion, but disposition index was higher in 287Gln carriers compared with Arg/Arg (p=0.022). Plasma EETs correlated with insulin sensitivity index (r=0.64, p=0.015 for total EETs) and were decreased in the metabolic syndrome. A genetic variant that results in decreased soluble epoxide hydrolase activity is associated with increased insulin sensitivity, as are higher EETs.

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Section: Discussionmentioning

confidence: 55%

Arg287Gln variant of EPHX2 and epoxyeicosatrienoic acids are associated with insulin sensitivity in humans

Ramirez

Shuey

Milne

et al. 2014

Prostaglandins & Other Lipid Mediators

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“…We now propose that this increase in PUFA-TAGs is caused by an increase in ACSL4 during HSC activation. Likewise, knock down of ACSL4 in insulin secreting INS 832/13 cells inhibited the incorporation of labeled AA into TAGs but not into PLs [25]. In contrast, overexpression of ACSL4 in arterial smooth muscle cells caused a relatively larger increase in incorporation of labeled AA into PLs as compared to TAGs [20].…”

Section: Discussionmentioning

confidence: 93%

Role of long-chain acyl-CoA synthetase 4 in formation of polyunsaturated lipid species in hepatic stellate cells

Tuohetahuntila

Spee

Kruitwagen

et al. 2015

Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biolog

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“…ACSL6, too, activates FA that are incorporated into phospholipids in neuronal cells (117), and an siRNA knockdown of Acsl1 reduces the levels of some phosphatidylcholine species that contain 20:4ω6 (93). In a related study in INS 832/13 cells, an siRNA knockdown of Acsl4 , but not Acsl5 , decreases basal and FA-stimulated glucose-stimulated insulin secretion by increasing the media content of epoxyeicosatrienoic acids (EETs) (91). In this study, the membrane content of EETs was reduced, suggesting that ACSL4 controls the intracellular content of unesterified EETs.…”

Section: Long-chain Acyl-coa Synthetasesmentioning

confidence: 99%

Acyl-CoA Metabolism and Partitioning

Grevengoed¹,

Klett

Coleman³

2014

Annu. Rev. Nutr.

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348

330

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Long-chain fatty acyl-CoAs are critical regulatory molecules and metabolic intermediates. The initial step in their synthesis is the activation of fatty acids by one of 13 long-chain acyl-CoA synthetase isoforms. These isoforms are regulated independently and have different tissue expression patterns and subcellular locations. Their acyl-CoA products regulate metabolic enzymes and signaling pathways, become oxidized to provide cellular energy, and are incorporated into acylated proteins and complex lipids like triacylglycerol, phospholipids, and cholesterol esters. Their differing metabolic fates are determined by a network of proteins that channel the acyl-CoAs towards or away from specific metabolic pathways and serve as the basis for partitioning. This review evaluates the evidence for acyl-CoA partitioning by reviewing experimental data on proteins that are believed to contribute to acyl-CoA channeling, the metabolic consequences of loss of these proteins, and the potential role of maladaptive acyl-CoA partitioning in the pathogenesis of metabolic disease and carcinogenesis.

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Diminished Acyl-CoA Synthetase Isoform 4 Activity in INS 832/13 Cells Reduces Cellular Epoxyeicosatrienoic Acid Levels and Results in Impaired Glucose-stimulated Insulin Secretion

Cited by 56 publications

References 48 publications

Arg287Gln variant of EPHX2 and epoxyeicosatrienoic acids are associated with insulin sensitivity in humans

Arg287Gln variant of EPHX2 and epoxyeicosatrienoic acids are associated with insulin sensitivity in humans

Role of long-chain acyl-CoA synthetase 4 in formation of polyunsaturated lipid species in hepatic stellate cells

Acyl-CoA Metabolism and Partitioning

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