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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: However, the exact mechanisms through which CLA mediates this effect remain to be elucidated.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.The data increases the understanding of the pathways regulated by CLA in atheroprotection, namely, inhibiting the progressive acquisition of a pro-inflammatory macrophage phenotype.

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: However, the exact mechanisms through which CLA mediates this effect remain to be elucidated.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.The data increases the understanding of the pathways regulated by CLA in atheroprotection, namely, inhibiting the progressive acquisition of a pro-inflammatory macrophage phenotype.

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