Abstract 19183: Overexpression of Apom in Liver Stimulates Formation of Larger, Apom/S1P-Enriched Plasma HDL

Abstract

Apolipoprotein M (ApoM), a lipocalin family member, preferentially associates with plasma HDL and binds plasma sphingosine 1-phosphate (S1P), a critical signaling molecule in immune homeostasis and endothelial barrier function. ApoM overexpression in ABCA1-expressing HEK293 cells stimulates larger nascent HDL particle formation compared to non apoM-expressing cells, but the in vivo role of apoM in HDL metabolism is poorly understood. To test whether hepatic apoM overexpression increases plasma HDL size, we generated liver-specific apoM transgenic (apoM Tg) mice displaying ~5-fold increase in plasma apoM levels compare to wild type (WT) mice. Although plasma HDL cholesterol concentrations were similar to WT mice, apoM Tg mice had larger plasma HDL particles, enriched in apoM, cholesteryl ester, lecithin:cholesterol acyltransferase and S1P. Despite the presence of larger plasma HDL particles in apoM Tg mice, in vivo macrophage reverse cholesterol transport capacity was similar to WT mice. ApoM Tg mice had ~5-fold increase in plasma S1P that was predominantly associated with larger plasma HDL particles. Primary hepatocytes from apoM Tg vs. WT mice generated larger nascent HDL particles, stimulated sphingolipid synthesis, and increased secretion of S1P. Chemical inhibition of ceramide synthase in hepatocytes stimulated S1P synthesis, but not secretion, suggesting that apoM is rate limiting in export of hepatocyte S1P. Our data suggest that liver-specific apoM overexpression: 1) generates large nascent HDLs and large plasma HDL particles that preferentially bind apoM and S1P, and 2) stimulates S1P synthesis for secretion into plasma. The unique apoM/S1P-enriched plasma HDL may serve to deliver S1P to extrahepatic tissues for atheroprotection or other as yet unidentified functions.