Hepatic ApoM overexpression stimulates formation of larger, ApoM/S1P-enriched plasma HDL [Metabolism]

December 6th, 2013 by Liu, M., Seo, J., Allegood, J., Bi, X., Zhu, X., Boudyguina, E., Gebre, A. K., Avni, D., Shah, D., Sorci-Thomas, M. G., Thomas, M. J., Shelness, G. S., Spiegel, S., Parks, J. S.

Apolipoprotein M (apoM), a lipocalin family member, preferentially associates with plasma HDL and binds plasma sphingosine-1-phosphate (S1P), a signaling molecule active in immune homeostasis and endothelial barrier function. ApoM overexpression in ABCA1-expressing HEK293 cells stimulated larger nascent HDL formation, compared to cells that did not express apoM; however, the in vivo role of apoM in HDL metabolism remains poorly understood. To test whether hepatic apoM overexpression increases plasma HDL size, we generated hepatocyte-specific apoM transgenic (apoM Tg) mice, which had ~3-5-fold increase in plasma apoM levels compared with wild-type mice. Although HDL cholesterol concentrations were similar to wild-type mice, apoM Tg mice had larger plasma HDLs enriched in apoM, cholesteryl ester, lecithin:cholesterol acyltransferase, and S1P. Despite the presence of larger plasma HDLs in apoM Tg mice, in vivo macrophage reverse cholesterol transport capacity was similar to that in wild-type mice. ApoM Tg mice had an ~5-fold increase in plasma S1P, which was predominantly associated with larger plasma HDLs. Primary hepatocytes from apoM Tg mice generated larger nascent HDLs and displayed increased sphingolipid synthesis and S1P secretion. Inhibition of ceramide synthases in hepatocytes increased cellular S1P levels, but not S1P secretion, suggesting that apoM is rate-limiting in the export of hepatocyte S1P. Our data indicate that hepatocyte-specific apoM overexpression: 1) generates larger nascent HDLs and larger plasma HDLs, which preferentially bind apoM and S1P; and 2) stimulates S1P biosynthesis for secretion. The unique apoM/S1P-enriched plasma HDL may serve to deliver S1P to extrahepatic tissues for atheroprotection and may have other as yet unidentified functions.