Key result
M1 macrophage polarization cuts LSR protein expression ~72% vs M2, with knockdown increasing basal glycolysis.
Why the study?
Macrophages depend on lipoprotein receptors to regulate lipid influx and metabolic state in atherosclerosis, and the role of the lipolysis stimulated lipoprotein receptor (LSR) in macrophage lipid handling needed to be determined.
Does macrophage polarization, foam cell transformation, or siRNA-mediated LSR knockdown alter LSR expression, lipoprotein uptake activity, and cellular glycolytic metabolism in murine macrophages?
Does macrophage polarization, foam cell transformation, or siRNA-mediated LSR knockdown alter LSR expression, lipoprotein uptake activity, and cellular glycolytic metabolism in murine macrophages?
This preclinical study demonstrates that reduced expression and activity of the lipolysis stimulated lipoprotein receptor (LSR) in pro-inflammatory M1 macrophages and foam cells is associated with reduced lipid influx and a metabolic shift toward increased basal glycolysis.
Answers are grounded in this paper and cite their sources.
M1-driven LSR loss may shift macrophage metabolism in plaques; leaves open its therapeutic targeting pending in vivo studies.
In atherosclerosis, monocyte-derived macrophages in the subendothelial space of the arterial wall, become lipid-laden and pro-inflammatory. Macrophages depend on lipoprotein receptors to regulate lipid influx, thereby shaping macrophage metabolic state and potentially dictating their phenotype. The lipolysis stimulated lipoprotein receptor, LSR, contributes to lipid homeostasis and was detected by immunofluorescence in aortic atherosclerotic plaques from ApoE-/- mice and by immunoblot in macrophages. The aim was to determine LSR’s role in macrophage lipid handling by studying LSR expression and activity before (M0) or after polarization of Raw 264.7 cells using LPS/IFNγ (M1) or IL-4/IL-13 (M2), respectively. LSR mRNA (0.48-fold, p < 0.001), protein levels (0.28-fold, p < 0.001) were significantly lower in M1 (iNOS+/MCP1+) as compared to M2 (CD206+/Arg1+) macrophages. LSR activity, measured as oleate-induced uptake of DiI-labelled LDL, was significantly lower in M1 as compared to M2 macrophages. siRNA-mediated LSR knockdown (87±4%, p < 0.01) in M0 cells led to significantly decreased expression of genes involved in lipid influx (LDL-R, LRP1) and transport (ABCA1), increased basal glycolysis and decreased glycolytic reserve, but without changes in inflammatory markers. Raw 264.7 macrophages transformation into foam cells by 24h incubation with oxidized LDL also led to reduced LSR activity and expression. We propose that the lower LSR expression and activity observed in M1 and foam cell macrophages contribute to reduced lipid influx and increased glycolytic state that is associated with pro-inflammatory M1 phenotype. This provides new insight towards understanding how these immune cells depend on lipoprotein receptors regulating their metabolic uptake.
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Vanotti et al. (2026) studied Atherosclerosis / macrophage lipid homeostasis. M1 macrophage polarization (LPS 100 ng/mL + IFNγ 20 ng/mL) or siRNA-mediated LSR knockdown vs. M2 macrophage polarization (IL-4 20 ng/mL + IL-13 20 ng/mL) or control siRNA was evaluated on LSR mRNA and protein expression levels in M1 vs M2 polarized macrophages (0.48-fold mRNA and 0.28-fold protein expression, p=<0.001). M1 macrophage polarization significantly reduced LSR mRNA (0.48-fold, p<0.001) and protein (0.28-fold, p<0.001) compared to M2, while LSR knockdown increased basal glycolysis.
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