5-Lipoxygenase–Activating Protein

Bäck, Magnus; Sultan, Ariane; Ovchinnikova, Olga; Hansson, Göran K.

doi:10.1161/01.res.0000264498.60702.0d

Cited by 105 publications

(48 citation statements)

References 13 publications

(15 reference statements)

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“…In addition, FLAP, together with 5-LO, is implicated in the pathology of atherosclerosis. Here, FLAP was found to be highly upregulated in the aortas of mice in a model of atherosclerosis, and its inhibition attenuated disease severity (38,39).…”

Section: Discussionmentioning

confidence: 90%

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: 90%

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

et al. 2015

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“…Furthermore, LTB 4 also induces chemotaxis of other immune cells, such as Tlymphocytes, which accumulate in the vicinity of 5-LOpositive macrophages [52]. In a mouse model combining hyperinflammation and hyperlipidemia, through selective abrogation of T-cell TGFβ signaling in ApoE −/− mice, a stimulatory effect of activated T-lymphocytes on LT synthesis has been demonstrated [54]. Activated T-lymphocytes upregulate the expression of FLAP in macrophages, leading to an increased LTB 4 formation [54].…”

Section: Atherosclerotic Plaque Formationmentioning

confidence: 99%

“…In a mouse model combining hyperinflammation and hyperlipidemia, through selective abrogation of T-cell TGFβ signaling in ApoE −/− mice, a stimulatory effect of activated T-lymphocytes on LT synthesis has been demonstrated [54]. Activated T-lymphocytes upregulate the expression of FLAP in macrophages, leading to an increased LTB 4 formation [54]. The increased LTB 4 formation that results from both monocyte recruitment and T-lymphocyte-mediated FLAP up-regulation, may lead to a vicious circle involving progressive recruitment of inflammatory cells and a maintained immune activation within the atherosclerotic lesion [29,54].…”

Section: Atherosclerotic Plaque Formationmentioning

confidence: 99%

“…Activated T-lymphocytes upregulate the expression of FLAP in macrophages, leading to an increased LTB 4 formation [54]. The increased LTB 4 formation that results from both monocyte recruitment and T-lymphocyte-mediated FLAP up-regulation, may lead to a vicious circle involving progressive recruitment of inflammatory cells and a maintained immune activation within the atherosclerotic lesion [29,54]. Selective targeting of LTB 4 signaling could be key in blocking this vicious circle, as suggested by the capacity of different anti-leukotriene treatment strategies to reduce atheroma macrophage and Tlymphocyte content in hyperlipidemic mice (Fig.…”

Section: Atherosclerotic Plaque Formationmentioning

confidence: 99%

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Leukotriene Signaling in Atherosclerosis and Ischemia

Bäck

2008

Cardiovasc Drugs Ther

121

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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).…”

mentioning

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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5-Lipoxygenase–Activating Protein

Abstract: Transforming growth factor-␤ (TGF-␤

Cited by 105 publications

References 13 publications

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

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

Leukotriene Signaling in Atherosclerosis and Ischemia

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

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