Abstract 716: Oxidized LDL Repurposes Mitochondria to Drive Immune Activation Through CD36-Regulated Fatty Acid Trafficking and Metabolism

Atherosclerosis is considered a pathophysiological process that is commonly associated with dyslipidemia, oxidative stress and low-grade chronic inflammation. Dys-regulated metabolisms are also commonly observed in macrophages, the major immune cell type contributing to atherosclerosis. However, how these atherogenic factors impact on macrophages leading to persistent immune activation remains elusive. In this study, we explored how the atherogenic ligand oxLDL affects the metabolic status of macrophages, which drives inflammatory activation in macrophages using a combination of conventional methods, newly developed techniques for measuring metabolic alterations, and next generation RNA Sequencing. In this study, we report that oxLDL induces a CD36-dependent metabolic switch from mitochondrial oxidative phosphorylation to glycolysis in macrophages. During this metabolic switch, mitochondria repurpose themselves for reactive oxygen species (ROS) production that promote NF-κB activation and pro-inflammatory cytokine production. Mechanistically, we showed that oxLDL-CD36 axis re-organized fatty acid metabolisms including up-regulating long-chain fatty acids trafficking into the mitochondria while down-regulating fatty acid oxidation. This ultimately led to mitochondrial fatty acid accumulation, which facilitated ROS generation. Using the athero-prone ApoE KO mice model, we demonstrated that during high fat diet challenge for the development of atherosclerosis, white blood cells mitochondrial ROS stimulation was predominantly induced in Ly6C + monocytes and correlated with CD36 expression, and pro-atherogenic cytokine production. Those phenomena were persistent throughout the 6-week high fat diet challenge period. However, knocking out cd36 in ApoE KO mice significantly attenuated diet-induced mitochondrial ROS as well as pro-atherogenic cytokine production. Taken together, we present evidences of a CD36-dependent molecular pathway linking hyperlipidemia, oxidative stress, and chronic inflammation under the atherogenic conditions and provide a novel potential therapeutic strategy against atherosclerosis.