ROLE OF HEPATIC APOLIPOPROTEIN M AND ATP-BINDING CASSETTE TRANSPORTER A1 (ABCA1) IN LIPID METABOLISM

Apolipoprotein M (ApoM) and ABCA1 are both expressed in hepatocytes, but their impact on lipid metabolism remains poorly defined. ApoM binds to plasma HDL via its retained signal peptide and transports sphingosine 1&ndash;phosphate (S1P). We found that liver&ndash;specific apoM transgenic mice had larger plasma HDLs enriched with apoM, cholesteryl ester, lecithin:cholesterol acyltransferase and S1P, but not enhanced macrophage reverse cholesterol transport compared to wild type mice. Hepatocytes from transgenic mice generated larger nascent HDLs and stimulated sphingolipid synthesis and S1P secretion. Inhibition of ceramide synthase significantly increased cellular but not media S1P in apoM Tg hepatocytes, suggesting that apoM is rate limiting for S1P secretion. Overexpression of apoM<super>Q22A</super>, a mutant form of apoM with a cleavable signal peptide, in HEK293 cells and in mice did not stimulate larger nascent or mature HDL formation, but its overexpression in hepatocytes had faster secretion of apoM<super>Q22A</super> and mobilization of cellular S1P than apoM<super>WT</super>. We conclude that hepatic apoM overexpression facilitates the generation of large, apoM/S1P&ndash;enriched plasma HDLs and that this activity is dependent on its signal peptide retention.

Grantor dc:publisher

Wake Forest University

Year dc:date.issued

2013

Author dc:creator

• Liu, Mingxia

• ABC transporter A1

Language dc:language.iso

en

Handle dc:identifier.uri

http://hdl.handle.net/10339/39029

OAI identifier oai:identifier

oai:wakespace.lib.wfu.edu:10339/39029