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Mitochondrial Metabolic Reprogramming by CD36 Signaling Drives Macrophage Inflammatory Responses. Circ Res 2019 12 06;125(12):1087-1102



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Pubmed Central ID




Scopus ID

2-s2.0-85076330129   34 Citations


RATIONALE: A hallmark of chronic inflammatory disorders is persistence of proinflammatory macrophages in diseased tissues. In atherosclerosis, this is associated with dyslipidemia and oxidative stress, but mechanisms linking these phenomena to macrophage activation remain incompletely understood.

OBJECTIVE: To investigate mechanisms linking dyslipidemia, oxidative stress, and macrophage activation through modulation of immunometabolism and to explore therapeutic potential targeting specific metabolic pathways.

METHODS AND RESULTS: Using a combination of biochemical, immunologic, and ex vivo cell metabolic studies, we report that CD36 mediates a mitochondrial metabolic switch from oxidative phosphorylation to superoxide production in response to its ligand, oxidized LDL (low-density lipoprotein). Mitochondrial-specific inhibition of superoxide inhibited oxidized LDL-induced NF-κB (nuclear factor-κB) activation and inflammatory cytokine generation. RNA sequencing, flow cytometry, 3H-labeled palmitic acid uptake, lipidomic analysis, confocal and electron microscopy imaging, and functional energetics revealed that oxidized LDL upregulated effectors of long-chain fatty acid uptake and mitochondrial import, while downregulating fatty acid oxidation and inhibiting ATP5A (ATP synthase F1 subunit alpha)-an electron transport chain component. The combined effect is long-chain fatty acid accumulation, alteration of mitochondrial structure and function, repurposing of the electron transport chain to superoxide production, and NF-κB activation. Apoe null mice challenged with high-fat diet showed similar metabolic changes in circulating Ly6C+ monocytes and peritoneal macrophages, along with increased CD36 expression. Moreover, mitochondrial reactive oxygen species were positively correlated with CD36 expression in aortic lesional macrophages.

CONCLUSIONS: These findings reveal that oxidized LDL/CD36 signaling in macrophages links dysregulated fatty acid metabolism to oxidative stress from the mitochondria, which drives chronic inflammation. Thus, targeting to CD36 and its downstream effectors may serve as potential new strategies against chronic inflammatory diseases such as atherosclerosis.

Author List

Chen Y, Yang M, Huang W, Chen W, Zhao Y, Schulte ML, Volberding P, Gerbec Z, Zimmermann MT, Zeighami A, Demos W, Zhang J, Knaack DA, Smith BC, Cui W, Malarkannan S, Sodhi K, Shapiro JI, Xie Z, Sahoo D, Silverstein RL


Yiliang Chen PhD Assistant Professor in the Medicine department at Medical College of Wisconsin
Weiguo Cui PhD Associate Professor in the Microbiology and Immunology department at Medical College of Wisconsin
Subramaniam Malarkannan PhD Professor in the Medicine department at Medical College of Wisconsin
Daisy Sahoo PhD Vice Chair, Professor in the Medicine department at Medical College of Wisconsin
Roy L. Silverstein MD Chair, Center Associate Director, Professor in the Medicine department at Medical College of Wisconsin
Brian C. Smith PhD Associate Professor in the Biochemistry department at Medical College of Wisconsin
Michael T. Zimmermann PhD Director, Assistant Professor in the Clinical and Translational Science Institute department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

CD36 Antigens
Cells, Cultured
Cellular Reprogramming
Mice, Inbred C57BL
Mice, Knockout
Oxidative Stress
Signal Transduction