Adipose Tissue 12/15 Lipoxygenase Pathway in Human Obesity and Diabetes

Lieb, David C.; Brotman, Joshua J.; Hatcher, Margaret; Aye, Myo S.; Cole, Banumathi K.; Haynes, Bronson A.; Wohlgemuth, Stephen D.; Fontana, Mark Alan; Beydoun, Hind A.; Nadler, Jerry L.; Dobrian, Anca D.

doi:10.1210/jc.2013-4461

Cited by 34 publications

(32 citation statements)

References 19 publications

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“…These effects combined with previous work by others suggest that 15(S)-HETE could potentially contribute to a variety of diseases like hypertension, atherosclerosis and cancer. Furthermore, 15-lipoxygenase metabolites have been shown to contribute to many other conditions, including obesity, diabetes and respiratory disease [40–42]. However, many details of 15(S)-HETE cell signal transduction mechanisms are not understood.…”

Section: Discussionmentioning

confidence: 99%

(5Z,11Z,15R)-15-Hydroxyeicosa-5,11-dien-13-ynoic acid: A stable isomer of 15(S)-HETE that retains key vasoconstrictive and antiproliferative activity

Pfister

Klimko

Conrow

2016

Prostaglandins & Other Lipid Mediators

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15(S)-Hydroxyeicosa-(5Z,8Z,11Z,13E)-tetraenoic acid (15(S)-HETE) is a metabolite of arachidonic acid that elicits a number of biological effects including vasoconstriction and angiogenesis. (5Z,11Z,15R)-15-Hydroxyeicosa-5,11-dien-13-ynoic acid (HETE analog 1) is a synthetic isomer of 15(S)-HETE that is much more stable to autoxidation. Using isometric recording of isolated pulmonary arteries from male and female rabbits, HETE analog 1 and 15(S)-HETE were found to elicit concentration-dependent contractions that were slightly greater in females compared to males. The maximal response in females was greater with 15(S)-HETE. HETE analog 1 and 15(S)-HETE increased [3H]-thymidine incorporation in vascular smooth muscle cells cultured from male rabbit pulmonary arteries; both the maximal response and potency were greater with 15(S)-HETE. In contrast, HETE analog 1 produced a concentration-dependent inhibition in proliferation and migration of human hormone-independent prostate carcinoma PC-3 cells. The protocol for synthesis of HETE analog 1 is reported. The stability of this substance and its similar biological profile to 15(S)-HETE support future studies in eicosanoid research.

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Section: Discussionmentioning

confidence: 99%

(5Z,11Z,15R)-15-Hydroxyeicosa-5,11-dien-13-ynoic acid: A stable isomer of 15(S)-HETE that retains key vasoconstrictive and antiproliferative activity

Pfister

Klimko

Conrow

2016

Prostaglandins & Other Lipid Mediators

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“…These changes are mediated via janus kinase (JNK) phosphorylation, with subsequent phosphorylation of IRS-1(Ser) and impaired phosphorylation of IRS-1(Tyr) and protein kinase B phosphorylation (Chakrabarti, Cole, Wen, Keller, & Nadler, 2009). Likewise, 12-LOX expression in visceral adipose tissue of patients with T2D correlated with an increase in IL-6 and IL-12 cytokines (Lieb et al, 2014). Similarly, 12-HETE treatment of mouse macrophage cell lines (J773A.1) induced IL-6 and TNF-α production.…”

Section: Nafld Pathogenesismentioning

confidence: 99%

Molecular mechanisms of nonalcoholic fatty liver disease: Potential role for 12-lipoxygenase

Samala

Tersey

Anderson³

et al. 2017

Journal of Diabetes and its Complications

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Nonalcoholic fatty liver disease (NAFLD) is a spectrum of pathologies associated with fat accumulation in the liver. NAFLD is the most common cause of liver disease in the United States, affecting up to a third of the general population. It is commonly associated with features of metabolic syndrome, particularly insulin resistance. NAFLD shares the basic pathogenic mechanisms with obesity and insulin resistance, such as mitochondrial, oxidative and endoplasmic reticulum stress. Lipoxygenases catalyze the conversion of poly-unsaturated fatty acids in the plasma membrane—mainly arachidonic acid and linoleic acid—to produce oxidized pro-inflammatory lipid intermediates. 12-Lipoxygenase (12-LOX) has been studied extensively in setting of inflammation and insulin resistance. As insulin resistance is closely associated with development of NAFLD, the role of 12-LOX in pathogenesis of NAFLD has received increasing attention in recent years. In this review we discuss the role of 12-LOX in NAFLD pathogenesis and its potential role in emerging new therapeutics.

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“…The human enzyme most involved in generating 12-S-HETE in islets is 12-LO and is encoded by the ALOX12 gene. In mice, the products of both Alox12 and Alox15 (platelet 12-LO and leucocyte 12-LO, respectively) generate 12-S-HETE [9]. The enzymes 5-lipoxygenase (5-LO) and cyclo-oxygenase also metabolise arachidonic acid; the former produces leukotrienes, the latter produces prostaglandins.…”

Section: Figmentioning

confidence: 99%

“…1) [6]. Increased production of 12-S-HETE in islets and adipose tissue has been reported in rodent models of type 1 and type 2 diabetes and in diabetic humans [8, 9]. This metabolite exerts pathogenic inflammatory effects by activating downstream cytokines such as IL-12 [10] or by activating the second messengers c-Jun N-terminal kinase and p38 mitogen-activated protein kinase (p38 MAPK) [11].…”

Section: Introduction [H1]mentioning

confidence: 99%

Lipids and immunoinflammatory pathways of beta cell destruction

et al. 2016

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Islet inflammation contributes to beta cell demise in both type 1 and type 2 diabetes. 12-Lipoxygenase (12-LO, gene expressed as ALOX12 in human and 12-Lo in rodents in this manuscript) produces proinflammatory metabolites such as 12(S)-hydroxyeicosatetraenoic acids through dioxygenation of polyunsaturated fatty acids. 12-LO was first implicated in diabetes when the increase in 12-Lo expression and 12(S)-hydroxyeicosatetraenoic acid was noted in rodent models of diabetes. Subsequently, germline 12-Lo−/− was shown to prevent the development of hyperglycemia in mouse models of type 1 diabetes and in high-fat fed mice. More recently, beta cell-specific 12-Lo−/− was shown to protect mice against hyperglycaemia after streptozotocin and a high-fat diet. In humans, 12-LO expression is increased in pancreatic islets of autoantibody-positive, type 1 diabetic and type 2 diabetic organ donors. Interestingly, the high expression of ALOX12 is associated with the alteration in first-phase glucose-stimulated insulin secretion in human type 2 diabetic islets. To further clarify the role of islet 12-LO in diabetes and to validate 12-LO as a therapeutic target of diabetes, we have studied selective pharmacologic inhibitors for 12-LO. The compounds we have identified show promise: they protect beta cell lines and human islets from apoptosis and preserve insulin secretion when challenged by proinflammatory cytokine mixture. Currently studies are underway to test the compounds in mouse models of diabetes. This review summarizes a presentation given at the ‘Islet inflammation in type 2 diabetes’ symposium at the 2015 annual meeting of the EASD. It is accompanied two other mini-reviews on topics from this symposium (by Simone Baltrusch, DOI: XXX and Marc Donath, DOI: XXX) and a commentary by the Session Chair, Piero Marchetti (DOI: XXX).

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Adipose Tissue 12/15 Lipoxygenase Pathway in Human Obesity and Diabetes

Abstract: ALOX 12 may have a critical role in regulation of inflammation in VAT in obesity and T2D. Selective ALOX 12 inhibitors may constitute a new approach to limit AT inflammation in human obesity.

Cited by 34 publications

References 19 publications

(5Z,11Z,15R)-15-Hydroxyeicosa-5,11-dien-13-ynoic acid: A stable isomer of 15(S)-HETE that retains key vasoconstrictive and antiproliferative activity

(5Z,11Z,15R)-15-Hydroxyeicosa-5,11-dien-13-ynoic acid: A stable isomer of 15(S)-HETE that retains key vasoconstrictive and antiproliferative activity

Molecular mechanisms of nonalcoholic fatty liver disease: Potential role for 12-lipoxygenase

Lipids and immunoinflammatory pathways of beta cell destruction

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