Location: Obesity and Metabolism ResearchTitle: Lack of myeloid Fatp1 increases atherosclerotic lesion size in Ldlr-/- mice
|Liyang, Zhao - University Of North Carolina|
|Cozzo, Alyssa - University Of North Carolina|
|Johnson, Amy - University Of North Carolina|
|Christensen, Taylor - University Of North Carolina|
|Freemerman, Alex - University Of North Carolina|
|Bear, James - University Of North Carolina|
|Rotty, Jeremy - University Of North Carolina|
|Makowski, Liza - University Of North Carolina|
Submitted to: Atherosclerosis
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 10/6/2017
Publication Date: 10/7/2017
Citation: Liyang, Z., Cozzo, A.J., Johnson, A.R., Christensen, T., Freemerman, A.J., Bear, J.E., Rotty, J.D., Bennett, B.J., Makowski, L. 2017. Lack of myeloid Fatp1 increases atherosclerotic lesion size in Ldlr-/- mice. Atherosclerosis. 266:182-189. https://doi.org/10.1016/j.atherosclerosis.2017.10.009.
Interpretive Summary: Cardiovascular diseases such as atherosclerosis are the cause of approximately 1 in 3 deaths within the United States and are the leading cause of death worldwide. inflammation is a critical component of atherosclerotic plaque. Our previous work indicated that there is a critical link between fatty acid transport/metabolism and inflammation in atherosclerosis, demonstrating the need to further understand novel regulators of MF substrate metabolism [16-19]. Because MF lipid metabolism plays a central role in the pathogenesis of atherosclerosis, we hypothesized that MFs with demonstrated blunted fatty acid metabolism and elevated glycolysis due to lack of Fatp1 would display increased atherogenesis. Herein, we report that while lack of hematopoietic Fatp1 led to no systemic alterations in systemic lipids, Fatp1-/-Ldlr-/- mice displayed greater plaque formation compared to Fatp1+/+Ldlr-/- mice . These data indicate an important link between fatty acid metabolism and inflammatory responses associated with cardiovascular disease.
Technical Abstract: Altered metabolism is an important regulator of macrophage (MF) phenotype, which contributes to inflammatory diseases such as atherosclerosis. Broadly, pro-inflammatory, classically-activated MFs (CAM) are glycolytic while alternatively-activated MFs (AAM) oxidize fatty acids, although there is profound metabolic flexibility and overlap in the CAM-AAM spectrum in vivo. We previously demonstrated that MF fatty acid transport protein 1 (FATP1) 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 MF metabolic reprogramming through FATP1 ablation affected the process of atherogenesis. We hypothesized that FATP1 limits MF-mediated inflammation during atherogenesis. Thus, mice lacking MF 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. Results Fatp1-/-Ldlr-/- mice exhibited significantly larger lesion area (1.7-fold) by en face and aortic sinus analysis compared to Fatp1+/+Ldlr-/- mice. 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. Conclusion MF Fatp1 limits atherogenesis and may be a viable target to metabolically reprogram MFs.