ALOX5AP expression, but not gene haplotypes, is associated with obesity and insulin resistance

Kaaman, Maria; Rydén, Mikael; Axelsson, Tomas; Nordström, Elisabet Arvidsson; Sicard, Audrey; Bouloumié, Anne; Langin, Dominique; Dahlman, Ingrid

doi:10.1038/sj.ijo.0803147

Cited by 64 publications

(46 citation statements)

References 29 publications

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“…For instance, FLAP is frequently overexpressed in the adipose tissue of patients with obesity and insulin resistance (36). According to this, FLAP is detectable in adipose tissue of lean mice and is overexpressed in high-fat-diet-induced obesity model mice and Zucker rats.…”

Section: Discussionmentioning

confidence: 99%

Lipoxin and resolvin biosynthesis is dependent on 5‐lipoxygenase activating protein

et al. 2015

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Resolution of acute inflammation is an active process coordinated by proresolving lipid mediators (SPMs) such as lipoxins (LXs) and resolvins (Rvs), which are formed by the concerted action of 2 lipoxygenases (LOs). Because the exact molecular mechanisms of SPM biosynthesis are not completely understood, we aimed to investigate LX and D-type Rv formation in human leukocytes and HEK293T cells overexpressing leukotriene (LT) pathway enzymes. Activity assays in precursor (15-hydroxyeicosatetraenoic acids, 17-HDoHE)-treated granulocytes [polymorphonuclear leukocytes (PMNLs)] showed a strict dependence of LXA 4 /RvD 1 biosynthesis on cell integrity, and incubation with recombinant human 5-LO did not lead to LX or Rv formation. Pharmacologic inhibition of 5-LO activating protein (FLAP) by MK-886 inhibited LXA 4 /RvD 1 biosynthesis in precursor-treated PMNLs (drug concentration causing 50% inhibition ∼0.3/0.2 mM), as did knockdown of the enzyme in MM6 cells, and precursor-treated HEK293T overexpressing 5-LO produced high amounts of LXA 4 only in the presence of FLAP. In addition, inhibition of cytosolic phospholipase A 2a (cPLA 2a ) interfered with LXA 4 / RvD 1 formation from exogenous precursors in PMNLs. Furthermore, inhibition of the LT synthases LTA 4 hydrolase and LTC 4 synthase in PMNL/platelet coincubations augmented LXA 4 levels. These findings show that several enzymes known to be involved in the biosynthesis of proinflammatory LTs, such as FLAP and cPLA 2a , also contribute to LX and Rv formation.-

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Section: Discussionmentioning

confidence: 99%

Lipoxin and resolvin biosynthesis is dependent on 5‐lipoxygenase activating protein

et al. 2015

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“…Leukotriene production may be upregulated in patients with obesity. 140,141 There is also preliminary evidence that genes, more common among the obese, may affect the leukotriene pathway. We previously determined the allele frequencies of the addition/ deletion promoter polymorphism in the ALOX5 gene among a population of lean and obese asthmatics.…”

Section: Airway Inflammationmentioning

confidence: 99%

Obesity, Nutrition, and Asthma in Children

Lang

2012

Pediatric Allergy, Immunology, and Pulmonology

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“…Their expression is increased in adipose tissue of obese patients and animals with insulin resistance (11,12,23,24). Nevertheless, mice deficient for ALOX5 present an increase in body weight and body fat content and are more prone to fat accumulation when fed an HFD (13,25,26).…”

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confidence: 99%

ALOX5AP Overexpression in Adipose Tissue Leads to LXA4 Production and Protection Against Diet-Induced Obesity and Insulin Resistance

et al. 2016

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Eicosanoids, such as leukotriene B4 (LTB4) and lipoxin A4 (LXA4), may play a key role during obesity. While LTB4 is involved in adipose tissue inflammation and insulin resistance, LXA4 may exert anti-inflammatory effects and alleviate hepatic steatosis. Both lipid mediators derive from the same pathway, in which arachidonate 5-lipoxygenase (ALOX5) and its partner, arachidonate 5-lipoxygenase–activating protein (ALOX5AP), are involved. ALOX5 and ALOX5AP expression is increased in humans and rodents with obesity and insulin resistance. We found that transgenic mice overexpressing ALOX5AP in adipose tissue had higher LXA4 rather than higher LTB4 levels, were leaner, and showed increased energy expenditure, partly due to browning of white adipose tissue (WAT). Upregulation of hepatic LXR and Cyp7a1 led to higher bile acid synthesis, which may have contributed to increased thermogenesis. In addition, transgenic mice were protected against diet-induced obesity, insulin resistance, and inflammation. Finally, treatment of C57BL/6J mice with LXA4, which showed browning of WAT, strongly suggests that LXA4 is responsible for the transgenic mice phenotype. Thus, our data support that LXA4 may hold great potential for the future development of therapeutic strategies for obesity and related diseases.

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ALOX5AP expression, but not gene haplotypes, is associated with obesity and insulin resistance

Cited by 64 publications

References 29 publications

Lipoxin and resolvin biosynthesis is dependent on 5‐lipoxygenase activating protein

Lipoxin and resolvin biosynthesis is dependent on 5‐lipoxygenase activating protein

Obesity, Nutrition, and Asthma in Children

ALOX5AP Overexpression in Adipose Tissue Leads to LXA4 Production and Protection Against Diet-Induced Obesity and Insulin Resistance

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