BACKGROUND AND AIMS:Altered metabolism is an important regulator of macrophage (MΦ) phenotype, which contributes to inflammatory diseases such as atherosclerosis. Broadly, pro-inflammatory, classically-activated MΦs (CAM) are glycolytic while alternatively-activated MΦs (AAM) oxidize fatty acids, although overlap exists. We previously demonstrated that MΦ fatty acid transport protein 1 (FATP1, Slc27a1) was necessary to maintain the oxidative and anti-inflammatory AAM phenotype in vivo in a model of diet-induced obesity. The aim of this study was to examine how MΦ metabolic reprogramming through FATP1 ablation affects the process of atherogenesis. We hypothesized that FATP1 limits MΦ-mediated inflammation during atherogenesis. Thus, mice lacking MΦ Fatp1 would display elevated formation of atherosclerotic lesions in a mouse model lacking the low-density lipoprotein (LDL) receptor (Ldlr-/-). METHODS:We transplanted bone marrow collected from Fatp1+/+ or Fatp1-/- mice into Ldlr-/- mice and fed chimeric mice a Western diet for 12 weeks. Body weight, blood glucose, and plasma lipids were measured. Aortic sinus and aorta lesions were quantified. Atherosclerotic plaque composition, oxidative stress, and inflammation were analyzed histologically. RESULTS:Compared to Fatp1+/+Ldlr-/- mice, Fatp1-/-Ldlr-/- mice exhibited significantly larger lesion area and elevated oxidative stress and inflammation in the atherosclerotic plaque. Macrophage and smooth muscle cell content did not differ by Fatp1 genotype. There were no significant systemic alterations in LDL, high-density lipoprotein (HDL), total cholesterol, or triacylglyceride, suggesting that the effect was local to the cells of the vessel microenvironment in a Fatp1-dependent manner. CONCLUSIONS:MΦ Fatp1 limits atherogenesis and may be a viable target to metabolically reprogram MΦs.

Macrophages (MΦs) are heterogeneous and metabolically flexible, with metabolism strongly affecting immune activation. A classic response to proinflammatory activation is increased flux through glycolysis with a downregulation of oxidative metabolism, whereas alternative activation is primarily oxidative, which begs the question of whether targeting glucose metabolism is a viable approach to control MΦ activation. We created a murine model of myeloid-specific glucose transporter GLUT1 (Slc2a1) deletion. Bone marrow-derived MΦs (BMDM) from Slc2a1^M-/- mice failed to uptake glucose and demonstrated reduced glycolysis and pentose phosphate pathway activity. Activated BMDMs displayed elevated metabolism of oleate and glutamine, yet maximal respiratory capacity was blunted in MΦ lacking GLUT1, demonstrating an incomplete metabolic reprogramming. Slc2a1^M-/- BMDMs displayed a mixed inflammatory phenotype with reductions of the classically activated pro- and anti-inflammatory markers, yet less oxidative stress. Slc2a1^M-/- BMDMs had reduced proinflammatory metabolites, whereas metabolites indicative of alternative activation-such as ornithine and polyamines-were greatly elevated in the absence of GLUT1. Adipose tissue MΦs of lean Slc2a1^M-/- mice had increased alternative M2-like activation marker mannose receptor CD206, yet lack of GLUT1 was not a critical mediator in the development of obesity-associated metabolic dysregulation. However, Ldlr^-/- mice lacking myeloid GLUT1 developed unstable atherosclerotic lesions. Defective phagocytic capacity in Slc2a1^M-/- BMDMs may have contributed to unstable atheroma formation. Together, our findings suggest that although lack of GLUT1 blunted glycolysis and the pentose phosphate pathway, MΦ were metabolically flexible enough that inflammatory cytokine release was not dramatically regulated, yet phagocytic defects hindered MΦ function in chronic diseases.