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Conjugated linoleic acid induces an atheroprotective macrophage MΦ2 phenotype and limits foam cell formation.

de Gaetano M, Alghamdi K, Marcone S, Belton O - J Inflamm (Lond) (2015)

Bottom Line: Conjugated linoleic acid (CLA) is a group of isomers of linoleic acid that differ in the position and/or geometry of their double bonds.However, the exact mechanisms through which CLA mediates this effect remain to be elucidated.In addition, cis-9,trans-11-CLA and CLA blend primes HPBMCs towards an anti-inflammatory MΦ2 phenotype, characterised by increased scavenger receptor (CD36) and efflux protein (ABCA-1) expression.

View Article: PubMed Central - PubMed

Affiliation: School of Biomedical and Biomolecular Science, UCD Conway Institute, University College Dublin, Dublin, Ireland.

ABSTRACT

Background: Atherosclerosis, the underlying cause of heart attack and strokes, is a progresive dyslipidemic and inflammatory disease where monocyte-derived macrophage cells play a pivotal role. Although most of the mechanisms that contribute to the progression of atherosclerosis have been identified, there is limited information on those governing regression. Conjugated linoleic acid (CLA) is a group of isomers of linoleic acid that differ in the position and/or geometry of their double bonds. We have previously shown that a specific CLA blend (80:20 cis-9,trans-11:trans-10,cis-12-CLA) induces regression of pre-established atherosclerosis in vivo, via modulation of monocyte/macrophage function. However, the exact mechanisms through which CLA mediates this effect remain to be elucidated.

Methods: Here, we address if CLA primes monocytes towards an anti-inflammatory MΦ2 macrophage and examine the effect of individual CLA isomers and the atheroprotective blend on monocyte-macrophage differentiation, cytokine generation, foam cell formation and cholesterol metabolism in human peripheral blood monocyte (HPBMC)-derived macrophages.

Results: cis-9,trans-11-CLA and the atheroprotective 80:20 CLA blend regulates expression of pro-inflammatory mediators and modulates the inflammatory cytokine profile of macrophages and foam cells. In addition, cis-9,trans-11-CLA and CLA blend primes HPBMCs towards an anti-inflammatory MΦ2 phenotype, characterised by increased scavenger receptor (CD36) and efflux protein (ABCA-1) expression. Furthermore, this altered macrophage phenotype impacts on foam cell formation, inhibiting ox-LDL accumulation and promoting cholesterol efflux via both PPARγ and LXRα dependent pathways.

Conclusion: The data increases the understanding of the pathways regulated by CLA in atheroprotection, namely, inhibiting the progressive acquisition of a pro-inflammatory macrophage phenotype.

No MeSH data available.


Related in: MedlinePlus

CLA increasedCD36andABCA-1expressionviaa PPARγ/LXRα mechanism. (a) RT-PCR analysis of SRA-1, CD36, ABCA-1, PPARγ and LXRα in HPBMC-derived macrophages pre-treated with c-9,t-11; t-10,c-12; CLA blend; OA; LA; TROG or T1317 and stimulated with ox-LDL for 4 hours to induce foam cell formation. CLA blend and c-9,t-11 increase CD36 and ABCA-1. Although t-10,c-12 has no effect on SR expression, it incresases ABCA-1, which is a generalized effect of linoleic acids. The same effect was observed with the parent compound LA. RT-PCR analysis of (b)CD36 and (c)ABCA-1 mRNA expression in PMA-induced macrophages treated with c-9,t-11, CLA blend and TROG alone or in combination with the PPARγ and LXRα antagonists (GW9662 and GSK2033, respectively). Pre-treatment with the antagonists attenuates or abolished the CLA-induced upregulation of both CD36 and ABCA-1, respectively. Statistical analysis of three independent experiments is expressed as fold change expression relative to DMSO control where *p < 0.05; **p < 0.01 and ***p < 0.001 or relative to the combination of the antagonist and the antagonist vs the agonist alone, where #p < 0.05 or ##p < 0.01.
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Fig3: CLA increasedCD36andABCA-1expressionviaa PPARγ/LXRα mechanism. (a) RT-PCR analysis of SRA-1, CD36, ABCA-1, PPARγ and LXRα in HPBMC-derived macrophages pre-treated with c-9,t-11; t-10,c-12; CLA blend; OA; LA; TROG or T1317 and stimulated with ox-LDL for 4 hours to induce foam cell formation. CLA blend and c-9,t-11 increase CD36 and ABCA-1. Although t-10,c-12 has no effect on SR expression, it incresases ABCA-1, which is a generalized effect of linoleic acids. The same effect was observed with the parent compound LA. RT-PCR analysis of (b)CD36 and (c)ABCA-1 mRNA expression in PMA-induced macrophages treated with c-9,t-11, CLA blend and TROG alone or in combination with the PPARγ and LXRα antagonists (GW9662 and GSK2033, respectively). Pre-treatment with the antagonists attenuates or abolished the CLA-induced upregulation of both CD36 and ABCA-1, respectively. Statistical analysis of three independent experiments is expressed as fold change expression relative to DMSO control where *p < 0.05; **p < 0.01 and ***p < 0.001 or relative to the combination of the antagonist and the antagonist vs the agonist alone, where #p < 0.05 or ##p < 0.01.

Mentions: To elucidate the mechanism through which CLA, by inducing an MΦ2 phenotype, inhibits foam cell formation, we next examined expression of the scavenger receptors SR-A1 and CD36 in human macrophage-derived foam cells (Figure 3a). Although CLA had no effect on SR-A1 expression, both c-9,t-11-CLA and CLA blend increased CD36 expression in the presence of ox-LDL (by 1.3 fold, p < 0.01 for both), whereas, neither t-10,c-12-CLA isomer nor either of the two fatty acid controls modulated CD36 expression.Figure 3


Conjugated linoleic acid induces an atheroprotective macrophage MΦ2 phenotype and limits foam cell formation.

de Gaetano M, Alghamdi K, Marcone S, Belton O - J Inflamm (Lond) (2015)

CLA increasedCD36andABCA-1expressionviaa PPARγ/LXRα mechanism. (a) RT-PCR analysis of SRA-1, CD36, ABCA-1, PPARγ and LXRα in HPBMC-derived macrophages pre-treated with c-9,t-11; t-10,c-12; CLA blend; OA; LA; TROG or T1317 and stimulated with ox-LDL for 4 hours to induce foam cell formation. CLA blend and c-9,t-11 increase CD36 and ABCA-1. Although t-10,c-12 has no effect on SR expression, it incresases ABCA-1, which is a generalized effect of linoleic acids. The same effect was observed with the parent compound LA. RT-PCR analysis of (b)CD36 and (c)ABCA-1 mRNA expression in PMA-induced macrophages treated with c-9,t-11, CLA blend and TROG alone or in combination with the PPARγ and LXRα antagonists (GW9662 and GSK2033, respectively). Pre-treatment with the antagonists attenuates or abolished the CLA-induced upregulation of both CD36 and ABCA-1, respectively. Statistical analysis of three independent experiments is expressed as fold change expression relative to DMSO control where *p < 0.05; **p < 0.01 and ***p < 0.001 or relative to the combination of the antagonist and the antagonist vs the agonist alone, where #p < 0.05 or ##p < 0.01.
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Related In: Results  -  Collection

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Fig3: CLA increasedCD36andABCA-1expressionviaa PPARγ/LXRα mechanism. (a) RT-PCR analysis of SRA-1, CD36, ABCA-1, PPARγ and LXRα in HPBMC-derived macrophages pre-treated with c-9,t-11; t-10,c-12; CLA blend; OA; LA; TROG or T1317 and stimulated with ox-LDL for 4 hours to induce foam cell formation. CLA blend and c-9,t-11 increase CD36 and ABCA-1. Although t-10,c-12 has no effect on SR expression, it incresases ABCA-1, which is a generalized effect of linoleic acids. The same effect was observed with the parent compound LA. RT-PCR analysis of (b)CD36 and (c)ABCA-1 mRNA expression in PMA-induced macrophages treated with c-9,t-11, CLA blend and TROG alone or in combination with the PPARγ and LXRα antagonists (GW9662 and GSK2033, respectively). Pre-treatment with the antagonists attenuates or abolished the CLA-induced upregulation of both CD36 and ABCA-1, respectively. Statistical analysis of three independent experiments is expressed as fold change expression relative to DMSO control where *p < 0.05; **p < 0.01 and ***p < 0.001 or relative to the combination of the antagonist and the antagonist vs the agonist alone, where #p < 0.05 or ##p < 0.01.
Mentions: To elucidate the mechanism through which CLA, by inducing an MΦ2 phenotype, inhibits foam cell formation, we next examined expression of the scavenger receptors SR-A1 and CD36 in human macrophage-derived foam cells (Figure 3a). Although CLA had no effect on SR-A1 expression, both c-9,t-11-CLA and CLA blend increased CD36 expression in the presence of ox-LDL (by 1.3 fold, p < 0.01 for both), whereas, neither t-10,c-12-CLA isomer nor either of the two fatty acid controls modulated CD36 expression.Figure 3

Bottom Line: Conjugated linoleic acid (CLA) is a group of isomers of linoleic acid that differ in the position and/or geometry of their double bonds.However, the exact mechanisms through which CLA mediates this effect remain to be elucidated.In addition, cis-9,trans-11-CLA and CLA blend primes HPBMCs towards an anti-inflammatory MΦ2 phenotype, characterised by increased scavenger receptor (CD36) and efflux protein (ABCA-1) expression.

View Article: PubMed Central - PubMed

Affiliation: School of Biomedical and Biomolecular Science, UCD Conway Institute, University College Dublin, Dublin, Ireland.

ABSTRACT

Background: Atherosclerosis, the underlying cause of heart attack and strokes, is a progresive dyslipidemic and inflammatory disease where monocyte-derived macrophage cells play a pivotal role. Although most of the mechanisms that contribute to the progression of atherosclerosis have been identified, there is limited information on those governing regression. Conjugated linoleic acid (CLA) is a group of isomers of linoleic acid that differ in the position and/or geometry of their double bonds. We have previously shown that a specific CLA blend (80:20 cis-9,trans-11:trans-10,cis-12-CLA) induces regression of pre-established atherosclerosis in vivo, via modulation of monocyte/macrophage function. However, the exact mechanisms through which CLA mediates this effect remain to be elucidated.

Methods: Here, we address if CLA primes monocytes towards an anti-inflammatory MΦ2 macrophage and examine the effect of individual CLA isomers and the atheroprotective blend on monocyte-macrophage differentiation, cytokine generation, foam cell formation and cholesterol metabolism in human peripheral blood monocyte (HPBMC)-derived macrophages.

Results: cis-9,trans-11-CLA and the atheroprotective 80:20 CLA blend regulates expression of pro-inflammatory mediators and modulates the inflammatory cytokine profile of macrophages and foam cells. In addition, cis-9,trans-11-CLA and CLA blend primes HPBMCs towards an anti-inflammatory MΦ2 phenotype, characterised by increased scavenger receptor (CD36) and efflux protein (ABCA-1) expression. Furthermore, this altered macrophage phenotype impacts on foam cell formation, inhibiting ox-LDL accumulation and promoting cholesterol efflux via both PPARγ and LXRα dependent pathways.

Conclusion: The data increases the understanding of the pathways regulated by CLA in atheroprotection, namely, inhibiting the progressive acquisition of a pro-inflammatory macrophage phenotype.

No MeSH data available.


Related in: MedlinePlus