Serine Hydroxymethyltransferase 2 Regulates Mitochondrial Function And Ceramide Metabolism In Macrophages During Atherosclerosis

Increasing evidence suggests a critical role for amino acid metabolism in cardiovascular disease, highlighting potential therapeutic targets and our need for further understanding. Plasma serine has been found to be a biomarker for cardiovascular disease, while glycine is negatively correlated with coronary artery disease. Furthermore, attenuated plasma glycine:serine is associated with unstable atherosclerotic plaques. Mitochondrial Serine hydroxymethyl transferase (SHMT) catalyzes the bulk formation of glycine from serine in most cell types and drives one-carbon metabolism in the cytosol (SHMT1) or mitochondria (SHMT2). SHMT2 is necessary for mitochondrial protein translation and critical in development since global knockout mice are nonviable. We found LPS-treated macrophages have reduced SHMT2 expression concomitant with attenuated intracellular glycine:serine. Deletion of macrophage SHMT2 in vitro enhanced intracellular serine, which contributes to the rate-limiting step of ceramide de novo biosynthesis. C16:0 ceramide is highly abundant in atherosclerotic plaques and is positively associated with plaque severity, and SHMT2-deleted macrophages treated with C16:0 fatty acid enhances intracellular ceramide. Furthermore, deletion of SHMT2 reduced mitochondrial respiration and enhanced glycolysis similar to LPS-treated macrophages. Moreover, we found SHMT2 is highly expressed in plaque-associated macrophages in both human and mouse atherosclerotic plaques. We therefore hypothesized that SHMT2 regulates macrophage inflammatory phenotype in atherosclerosis through alterations in mitochondrial function and ceramide biosynthesis. To determine whether macrophage-expressed SHMT2 contributes to atherosclerosis, we developed a novel Shmt2 -floxed mouse crossed with LysM-Cre ( Shmt2 MKO ) and Apoe -/- mice. After 12 weeks on Western diet, we observed no differences in plasma glycine:serine or circulating lipids. Nevertheless, Shmt2 MKO / Apoe -/- mice had significantly enhanced plaque area compared to littermate controls. Our findings, representing the first investigation of conditional SHMT2 knockout mice, suggest a novel immunometabolic role for SHMT2 in macrophages in atherosclerosis.