The apoA-I (apolipoprotein A-I) mimetic peptide 4F favours the differentiation of human monocytes to an alternatively activated M2 phenotype. The goal of the present study was to test whether the 4F-mediated differentiation of MDMs (monocyte-derived macrophages) requires the induction of an oxidative metabolic programme. 4F treatment induced several genes in MDMs that play an important role in lipid metabolism, including PPARγ (peroxisome-proliferator-activated receptor γ) and CD36. Addition of 4F was associated with a significant increase in FA (fatty acid) uptake and oxidation compared with vehicle treatment. Mitochondrial respiration was assessed by measurement of the OCR (oxygen-consumption rate). 4F increased basal and ATP-linked OCR as well as maximal uncoupled mitochondrial respiration. These changes were associated with a significant increase in ΔΨm (mitochondrial membrane potential). The increase in metabolic activity in 4F-treated MDMs was attenuated by etomoxir, an inhibitor of mitochondrial FA uptake. Finally, addition of the PPARγ antagonist T0070907 to 4F-treated MDMs reduced the expression of CD163 and CD36, cell-surface markers for M2 macrophages, and reduced basal and ATP-linked OCR. These results support our hypothesis that the 4F-mediated differentiation of MDMs to an anti-inflammatory phenotype is due, in part, to an increase in FA uptake and mitochondrial oxidative metabolism.
- apoA-I mimetic peptide
- fatty acid oxidation
- macrophage polarization
- mitochondrial respiration
- oxygen consumption rate
Abbreviations: ABC, ATP-binding cassette transporter; ACO, aconitase; apoA-I, apolipoprotein A-I; ATF3, activating transcription factor 3; CPT1, carnitine palmitoyltransferase 1; FA, fatty acid; FABP, fatty-acid-binding protein; FCCP, carbonyl cyanide p-trifluoromethoxyphenylhydrazone; HDL, high-density lipoprotein; IL, interleukin; LPL, lipoprotein lipase; LXR, liver X receptor; NF-κB, nuclear factor κB; OCR, oxygen-consumption rate; PE, phycoerythrin; PGC-1, PPARγ co-activator 1; PPARγ, peroxisome-proliferator-activated receptor γ; qRT-PCR, quantitative real-time PCR; SDHB, succinate dehydrogenase subunit B; TMRM, tetramethylrhodamine methyl ester; VDAC, voltage-dependent anion channel; ΔΨm, mitochondrial membrane potential
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