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

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abstract
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–phosphate (S1P). We found that liver–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 apoMQ22A, 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 apoMQ22A and mobilization of cellular S1P than apoMWT. We conclude that hepatic apoM overexpression facilitates the generation of large, apoM/S1P–enriched plasma HDLs and that this activity is dependent on its signal peptide retention.
subject
ABC transporter A1
apoM
lipid metabolism
S1P
Sphingolipid metabolism
triglyceride metabolism
contributor
Liu, Mingxia (author)
Parks, John S (committee chair)
Shelness, Gregory S (committee member)
Parks, Griffith (committee member)
Rudel, Lawrence L (committee member)
Sorci-Thomas, Mary G (committee member)
date
2013-08-23T08:35:18Z (accessioned)
2017-08-23T08:30:09Z (available)
2013 (issued)
degree
Molecular Pathology (discipline)
embargo
2017-08-23 (terms)
identifier
http://hdl.handle.net/10339/39029 (uri)
language
en (iso)
publisher
Wake Forest University
title
ROLE OF HEPATIC APOLIPOPROTEIN M AND ATP-BINDING CASSETTE TRANSPORTER A1 (ABCA1) IN LIPID METABOLISM
type
Dissertation

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