Lipoxygenase Pathway in Islet Endocrine Cells. OXIDATIVE METABOLISM OF ARACHIDONIC ACID PROMOTES INSULIN RELEASE

Metz, Stewart A.; VanRollins, Mike; Strife, Robert J.; Fujimoto, Wilfred Y.; Robertson, R. Paul

doi:10.1172/jci110868

Cited by 120 publications

(48 citation statements)

References 62 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We now provide evidence that the 5-LO/LT pathway is another mechanism by which such processes are regulated. Importantly, our observations are in agreement with a series of earlier studies carried out by Metz et al demonstrating that lipoxygenase inhibitors decrease glucose-stimulated insulin secretion in a dose-dependent manner [27,28] and that arachidonic acid metabolites play a role as 'third messengers' for hormone release [29,30]. More recently, Prasad and colleagues have shown that 12/15-LO, a related enzyme that also metabolises arachidonic acid, influences beta cell function and insulin secretion as well [31].…”

Section: Discussionsupporting

confidence: 92%

Identification of ALOX5 as a gene regulating adiposity and pancreatic function

et al. 2008

View full text Add to dashboard Cite

Aims/hypothesis We previously used an integrative genetics approach to demonstrate that 5-lipoxygenase (5-LO) deficiency in mice (Alox5 −/− ) protects against atherosclerosis despite increasing lipid levels and fat mass. In the present study, we sought to further examine the role of 5-LO in adiposity and pancreatic function. Methods Alox5 −/− and wild-type (WT) mice were characterised with respect to adiposity and glucose/insulin metabolism using in vivo and in vitro approaches. The role of ALOX5 in pancreatic function in human islets was assessed through short interfering RNA (siRNA) knockdown experiments. Results Beginning at 12 weeks of age, Alox5 −/− mice had significantly increased fat mass, plasma leptin levels and fasting glucose levels, but lower fasting insulin levels (p< 0.05). Although Alox5 −/− mice did not exhibit insulin resistance, they had impaired insulin secretion in response to a bolus glucose injection. Histological analyses revealed Diabetologia (2008) that Alox5 −/− mice had increased islet area, beta cell nuclear size, and numbers of beta cells/mm 2 islet (p < 0.05), indicative of both hyperplasia and hypertrophy. Basal and stimulated insulin secretion in isolated Alox5 −/− islets were significantly lower than in WT islets (p <0.05) and accompanied by a three-to fivefold decrease in the expression of the genes encoding insulin and pancreatic duodenal homeobox 1 (Pdx1). Direct perturbation of ALOX5 in isolated human islets with siRNA decreased insulin and PDX1 gene expression by 50% and insulin secretion by threefold (p<0.05). Conclusions/interpretation These results provide strong evidence for pleiotropic metabolic effects of 5-LO on adiposity and pancreatic function and may have important implications for therapeutic strategies targeting this pathway for the treatment of cardiovascular disease.

show abstract

Section: Discussionsupporting

confidence: 92%

Identification of ALOX5 as a gene regulating adiposity and pancreatic function

et al. 2008

View full text Add to dashboard Cite

show abstract

“…12LO was initially thought to be physiologically important in regulating glucose-stimulated insulin release in pancreatic islets of Langerhans [10][11][12][13]. More recent evidence has suggested that 12LO plays a role in inflammation and metabolic-stress-induced islet functional abnormalities.…”

Section: Introductionmentioning

confidence: 99%

“…Therefore, 12LO may have profound effects on cell metabolism and survival [24,25]. In addition, 12LO products are recognised as intracellular signalling molecules capable of activating specific protein kinases [26,27], translocating to specified cellular compartments [10], or modifying gene expression. Recent data also show that macrophages from the 12LO-null mouse lack IL-12 expression and production [28].…”

Section: Introductionmentioning

confidence: 99%

Activation of 12-lipoxygenase in proinflammatory cytokine-mediated beta cell toxicity

et al. 2005

View full text Add to dashboard Cite

Aims/hypothesis: Beta cell inflammation and cytokine-induced toxicity are central to autoimmune diabetes development. Lipid mediators generated upon lipoxygenase (LO) activation can participate in inflammatory pathways. 12LO-deficient mice are resistant to streptozotocin-induced diabetes. This study sought to characterise the cellular processes involving 12LO-activation lipid inflammatory mediator production in cytokine-treated pancreatic beta cells. Methods: Islets and beta cell lines were treated with a combination of IL-1β, IFN-γ and TNF-α, or the 12LO product 12(S)-hydroxyeicosatetraenoic acid (HETE). Insulin secretion was measured using an enzyme immunoassay, and cell viability was evaluated using an in situ terminal deoxynucleotidyl transferase-mediated dUTP nick-end labelling assay. 12LO activity was evaluated and 12LO protein levels were determined using immunoblotting with a selective leucocyte type 12LO antibody. Cellular localisation of 12LO was evaluated using immunocytochemistry. Results: Basal expression of leucocyte type 12LO protein was found in human and mouse islets and in several rodent beta cell lines. In mouse β-TC3 cells, and in human islets, cytokines induced release of 12-HETE within 30 min. Cytokine addition also induced a rapid translocation of 12LO protein from the cytosol to the nucleus of β-TC3 cells as shown by subcellular fractionation and immunostaining. Cytokine-induced cell death and inhibition of insulin secretion were partially reversed by baicalein, a 12LO inhibitor. 12(S)-HETE inhibited β-TC3 cell insulin release in a time-and concentration-dependent manner. Incubating β-TC3 cells with 100 nmol/l of 12(S)-HETE resulted in a 57% reduction in basal insulin release (6 h), and a 17% increase in cell death (18 h) as compared with untreated cells. 12(S)-HETE activated the stress-activated protein kinase c-Jun N-terminal kinase and p38 within 15 min, as judged by increased kinase protein phosphorylation. Conclusions/interpretation: The data suggest that inflammatory cytokines rapidly activate 12LO and show for the first time that cytokines induce 12LO translocation. The effects of 12-HETE on insulin secretion, cytotoxicity and kinase activation were similar to the effects seen with cytokines. The results provide mechanistic information of cytokine-induced toxic effects on pancreatic beta cells and support the hypothesis that blocking 12LO activation could provide a new therapeutic way to protect pancreatic beta cells from autoimmune injury.

show abstract

“…Isolated pancreatic islets from rats and humans convert endogenous arachidonic acid to oxygenated metabolites, and islet eicosanoid synthesis is stimulated by insulin secretagogues (1)(2)(3)(4)(5)(6)(7)(8)(9)(10). The most abundant islet eicosanoids are the cyclooxygenase product PGE 2 1 and the 12-lipoxygenase product 12-hydroxy- (5,8,10,14)-eicosatetraenoic acid .…”

mentioning

confidence: 99%

“…Fuel insulin secretagogues stimulate islet 12-HETE production; exogenous 12-HPETE, the precursor of 12-HETE, stimulates insulin secretion (1); and pharmacologic inhibitors of 12-lipoxygenase suppress both 12-HETE production and insulin secretion with identical concentration dependences (1)(2)(3)(4)(5)(6)(7)(8). Islet 12-HETE consists exclusively of the S-enantiomer, indicating enzymatic synthesis (9), and immunochemical analyses indicate that islet 12-lipoxygenase is selectively expressed in ␤-cells but not in ␣-cells or in pancreatic exocrine cells (18).…”

mentioning

confidence: 99%

Interleukin-1 Enhances Pancreatic Islet Arachidonic Acid 12-Lipoxygenase Product Generation by Increasing Substrate Availability through a Nitric Oxide-dependent Mechanism

Ramanadham

Corbett

et al. 1996

Journal of Biological Chemistry

View full text Add to dashboard Cite

Interleukin-1 (IL-1) impairs insulin secretion from pancreatic islets and may contribute to the pathogenesis of insulin-dependent diabetes mellitus. IL-1 increases islet expression of nitric oxide (NO) synthase, and the resultant overproduction of NO participates in inhibition of insulin secretion because NO synthase inhibitors, e.g. N G -monomethyl-arginine (NMMA), prevent this inhibition. While exploring effects of IL-1 on islet arachidonic acid metabolism, we found that IL-1 increases islet production of the 12-lipoxygenase product 12-hydroxyeicosatetraenoic acid 12-(HETE). This effect requires NO production and is prevented by NMMA. Exploration of the mechanism of this effect indicates that it involves increased availabilty of the substrate arachidonic acid rather than enhanced expression of 12-lipoxygenase. Evidence supporting this conclusion includes the facts that IL-1 does not increase islet 12-lipoxygenase protein or mRNA levels and does not enhance islet conversion of exogenous arachidonate to 12-HETE. Mass spectrometric stereochemical analyses nonetheless indicate that 12-HETE produced by IL-1-treated islets consists only of the S-enantiomer and thus arises from enzyme action. IL-1 does enhance release of nonesterified arachidonate from islets, as measured by isotope dilution mass spectrometry, and this effect is suppressed by NMMA and mimicked by the NO-releasing compound 3-morpholinosydnonimine. Although IL-1 increases neither islet phospholipase A 2 (PLA 2 ) activities nor mRNA levels for cytosolic or secretory PLA 2 , a suicide substrate which inhibits an islet Ca 2؉ -independent PLA 2 prevents enhancement of islet arachidonate release by IL-1. IL-1 also impairs esterification of [ 3 H 8 ]arachidonate into islet phospholipids, and this effect is prevented by NMMA and mimicked by the mitochondrial ATP-synthase inhibitor oligomycin. Experiments with exogenous substrates indicate that NMMA does not inhibit and that the NO-releasing compound does not activate islet 12-lipoxygenase or PLA 2 activities. These results indicate that a novel action of NO is to increase levels of nonesterified arachidonic acid in islets.

show abstract

Lipoxygenase Pathway in Islet Endocrine Cells. OXIDATIVE METABOLISM OF ARACHIDONIC ACID PROMOTES INSULIN RELEASE

Cited by 120 publications

References 62 publications

Identification of ALOX5 as a gene regulating adiposity and pancreatic function

Identification of ALOX5 as a gene regulating adiposity and pancreatic function

Activation of 12-lipoxygenase in proinflammatory cytokine-mediated beta cell toxicity

Interleukin-1 Enhances Pancreatic Islet Arachidonic Acid 12-Lipoxygenase Product Generation by Increasing Substrate Availability through a Nitric Oxide-dependent Mechanism

Contact Info

Product

Resources

About