Hepatic apolipoprotein M (apoM) overexpression stimulates formation of larger apoM/sphingosine 1-phosphate-enriched plasma high density lipoprotein. J Biol Chem 2014 Jan 31;289(5):2801-14
Date
12/10/2013Pubmed ID
24318881Pubmed Central ID
PMC3908412DOI
10.1074/jbc.M113.499913Scopus ID
2-s2.0-84893431254 (requires institutional sign-in at Scopus site) 75 CitationsAbstract
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 with 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 an ∼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 generates larger nascent HDLs and larger plasma HDLs, which preferentially bind apoM and S1P, and 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.
Author List
Liu M, Seo J, Allegood J, Bi X, Zhu X, Boudyguina E, Gebre AK, Avni D, Shah D, Sorci-Thomas MG, Thomas MJ, Shelness GS, Spiegel S, Parks JSAuthor
Mary Sorci Thomas PhD Professor in the Medicine department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AnimalsApolipoproteins
Apolipoproteins E
Apolipoproteins M
Female
Hepatocytes
Humans
Lipocalins
Lipoproteins, HDL
Liver
Lysophospholipids
Macrophages
Male
Mice
Mice, Inbred C57BL
Mice, Inbred DBA
Mice, Transgenic
Particle Size
Phosphatidylcholine-Sterol O-Acyltransferase
Sphingosine
