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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 play a key role in the pathogenesis of atherosclerosis. Metabolic programs powered by glucose or lipid enable macrophages to elicit pro- or anti-inflammatory responses, respectively. Although the chronic inflammatory feature of atherosclerosis has been well-established, the role of macrophage substrate metabolism in atherogenesis remains unclear. We previously demonstrated that macrophages with elevated GLUT1-mediated glucose metabolism have an increased inflammatory response. Therefore, we created a novel macrophage GLUT1-deficient murine model by crossing GLUT1 floxed to LysM-Cre mice. Recent work suggests that lack of GLUT1 reduces the pro-inflammatory response and the ability for GLUT1-/- macrophages to polarize to the classically activated state in vitro. Therefore, the objective of this study was to examine how macrophage metabolic reprogramming affects the development of atherosclerosis. We hypothesized that macrophages with restricted glucose metabolism due to lack of glucose transporter GLUT1 will have reduced pro-inflammatory activation during atherogenesis. We transplanted bone marrow from Glut1MΦfl/fl or Glut1MΦ-/- mice into Ldlr-/- mice and fed mice a Western diet for 12 weeks. Glut1MΦfl/fl Ldlr-/- or Glut1MΦ-/- Ldlr-/- chimeric mice did not exhibit significant differences in body weight, body composition, blood pressure, fasting blood glucose, or triacylglycerol and LDL and HDL cholesterol. Digital histology analysis of Oil Red O stained slides indicated that deleting macrophage GLUT1 did not affect total lesion area in aortic root; however, mice with blunted glucose metabolism displayed more and larger necrotic cores. Ongoing studies are investigating apoptosis and phagocytic capacity of macrophages with and without GLUT1 to elucidate the roles of macrophage glucose metabolism on the morphology of atherosclerotic lesion. In summary, we observed that mice lacking macrophage GLUT1 developed increased necrotic cores in lesions of the aorta root relative to mice with wild type macrophage GLUT1 which suggests that maintenance of atherosclerotic lesion stability may be regulated by glucose-dependent mechanisms.