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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 reduces intracellular cholesterol content of human macrophage derived foam cells. HBPMCs-derived M-CSF stimulated macrophages, following treatment with c-9,t-11-CLA, t-10,c-12-CLA, CLA blend (80:20 c-9,t-11:t-10,c-12), OA, LA or TROG were ox-LDL loaded for 4 hours and cholesterol content measured by enzymatic assay. CLA blend and c-9,t-11-CLA significantly decrease the levels of both total cholesterol (TC) and free cholesterol (FC), whilst, t-10,c-12-CLA and OA decrease the FC fraction. The effect of CLA on cholesterol trafficking is regulated by a dual mechanism involving PPARγ/LXRα-dependent. Data are expressed as % of TC or FC content over vehicle control, where *p < 0.05, **p < 0.01 and are the mean of three independent experiments.
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Fig4: CLA reduces intracellular cholesterol content of human macrophage derived foam cells. HBPMCs-derived M-CSF stimulated macrophages, following treatment with c-9,t-11-CLA, t-10,c-12-CLA, CLA blend (80:20 c-9,t-11:t-10,c-12), OA, LA or TROG were ox-LDL loaded for 4 hours and cholesterol content measured by enzymatic assay. CLA blend and c-9,t-11-CLA significantly decrease the levels of both total cholesterol (TC) and free cholesterol (FC), whilst, t-10,c-12-CLA and OA decrease the FC fraction. The effect of CLA on cholesterol trafficking is regulated by a dual mechanism involving PPARγ/LXRα-dependent. Data are expressed as % of TC or FC content over vehicle control, where *p < 0.05, **p < 0.01 and are the mean of three independent experiments.

Mentions: To address our hypothesis, we investigated the effect of CLA on intracellular cholesterol trafficking. To this end, HBPMCs-derived MCSF-induced macrophages were analysed for intracellular cholesterol content, following CLA treatment and subsequent ox-LDL loading, using the Amplex red cholesterol assay. Subsequently, we measured the fluorescent signals generated by the activity of both cholesterol oxidase and esterase, calculating the content of both free cholesterol (FC) and total cholesterol (TC). c-9,t-11-CLA significantly decreased the levels of TC by 29 ± 9% (p < 0.05) and of FC by 36 ± 5% (p < 0.01) and CLA blend reduced TC by 36 ± 11% (p < 0.05) and FC by 44 ± 7% (p < 0.01). Importantly, neither the t-10,c-12-CLA isomer nor OA had any significant effect on TC although they both reduced FC. The PPARγ agonist TROG also reduced TC by 28 ± 7% (p < 0.05) and FC by 39 ± 12% (p < 0.05) and the LXRα agonist T1317 reduced TC by 65 ± 12% (p < 0.01) and FC by 89 ± 2% (p < 0.001). This data confirms that the overall effect of the c-9,t-11-CLA isomer and the CLA blend on cholesterol trafficking is regulated by a dual mechanism: a PPARγ-dependent pathway, controlling cholesterol influx (as previously confirmed by the regulation of CD36) and an LXRα-dependent mechanism, directly influencing the cholesterol efflux (through upregulation of the efflux protein ABCA-1, as previously shown) (Figure 4).Figure 4


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 reduces intracellular cholesterol content of human macrophage derived foam cells. HBPMCs-derived M-CSF stimulated macrophages, following treatment with c-9,t-11-CLA, t-10,c-12-CLA, CLA blend (80:20 c-9,t-11:t-10,c-12), OA, LA or TROG were ox-LDL loaded for 4 hours and cholesterol content measured by enzymatic assay. CLA blend and c-9,t-11-CLA significantly decrease the levels of both total cholesterol (TC) and free cholesterol (FC), whilst, t-10,c-12-CLA and OA decrease the FC fraction. The effect of CLA on cholesterol trafficking is regulated by a dual mechanism involving PPARγ/LXRα-dependent. Data are expressed as % of TC or FC content over vehicle control, where *p < 0.05, **p < 0.01 and are the mean of three independent experiments.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
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getmorefigures.php?uid=PMC4340802&req=5

Fig4: CLA reduces intracellular cholesterol content of human macrophage derived foam cells. HBPMCs-derived M-CSF stimulated macrophages, following treatment with c-9,t-11-CLA, t-10,c-12-CLA, CLA blend (80:20 c-9,t-11:t-10,c-12), OA, LA or TROG were ox-LDL loaded for 4 hours and cholesterol content measured by enzymatic assay. CLA blend and c-9,t-11-CLA significantly decrease the levels of both total cholesterol (TC) and free cholesterol (FC), whilst, t-10,c-12-CLA and OA decrease the FC fraction. The effect of CLA on cholesterol trafficking is regulated by a dual mechanism involving PPARγ/LXRα-dependent. Data are expressed as % of TC or FC content over vehicle control, where *p < 0.05, **p < 0.01 and are the mean of three independent experiments.
Mentions: To address our hypothesis, we investigated the effect of CLA on intracellular cholesterol trafficking. To this end, HBPMCs-derived MCSF-induced macrophages were analysed for intracellular cholesterol content, following CLA treatment and subsequent ox-LDL loading, using the Amplex red cholesterol assay. Subsequently, we measured the fluorescent signals generated by the activity of both cholesterol oxidase and esterase, calculating the content of both free cholesterol (FC) and total cholesterol (TC). c-9,t-11-CLA significantly decreased the levels of TC by 29 ± 9% (p < 0.05) and of FC by 36 ± 5% (p < 0.01) and CLA blend reduced TC by 36 ± 11% (p < 0.05) and FC by 44 ± 7% (p < 0.01). Importantly, neither the t-10,c-12-CLA isomer nor OA had any significant effect on TC although they both reduced FC. The PPARγ agonist TROG also reduced TC by 28 ± 7% (p < 0.05) and FC by 39 ± 12% (p < 0.05) and the LXRα agonist T1317 reduced TC by 65 ± 12% (p < 0.01) and FC by 89 ± 2% (p < 0.001). This data confirms that the overall effect of the c-9,t-11-CLA isomer and the CLA blend on cholesterol trafficking is regulated by a dual mechanism: a PPARγ-dependent pathway, controlling cholesterol influx (as previously confirmed by the regulation of CD36) and an LXRα-dependent mechanism, directly influencing the cholesterol efflux (through upregulation of the efflux protein ABCA-1, as previously shown) (Figure 4).Figure 4

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