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Journal of Lipid Research, Vol. 45, 1122-1131, June 2004
Copyright © 2004 by American Society for Biochemistry and Molecular Biology

ABCA1-dependent lipid efflux to apolipoprotein A-I mediates HDL particle formation and decreases VLDL secretion from murine hepatocytes

Daisy Sahoo^*,, Timothy C. Trischuk^*, Teddy Chan, Victor A. B. Drover, Samuel Ho^*, Giovanna Chimini, Luis B. Agellon, Ricky Agnihotri^*, Gordon A. Francis^1,2,, and Richard Lehner^1,2,*,**

^* Departments of Pediatrics, CIHR Group on Molecular and Cell Biology of Lipids, University of Alberta, Edmonton, Alberta, Canada
Medicine, CIHR Group on Molecular and Cell Biology of Lipids, University of Alberta, Edmonton, Alberta, Canada
Biochemistry, CIHR Group on Molecular and Cell Biology of Lipids, University of Alberta, Edmonton, Alberta, Canada
^** Cell Biology, CIHR Group on Molecular and Cell Biology of Lipids, University of Alberta, Edmonton, Alberta, Canada
Centre d'Immunologie, INSERM-CNRS de Marseille Luminy, Marseille, France

² To whom correspondence should be addressed. e-mail: gordon.francis{at}ualberta.ca (G.A.F.); richard.lehner{at}ualberta.ca (R.L.)

High levels of expression of the ATP binding cassette transporter A1 (ABCA1) in the liver and the need to over- or underexpress hepatic ABCA1 to impact plasma HDL levels in mice suggest a major role of the liver in HDL formation and in determining circulating HDL levels. Cultured murine hepatocytes were used to examine the role of hepatic ABCA1 in mediating the lipidation of apolipoprotein A-I (apoA-I) for HDL particle formation. Exogenous apoA-I stimulated cholesterol efflux to the medium from wild-type hepatocytes, but not from ABCA1-deficient (abca1^–/–) hepatocytes. ApoA-I induced the formation of new HDL particles and enhanced the lipidation of endogenously secreted murine apoA-I in ABCA1-expressing but not abca1^–/– hepatocytes. ABCA1-dependent cholesterol mobilization to apoA-I increased new cholesterol synthesis, indicating depletion of the regulatory pool of hepatocyte cholesterol during HDL formation. Secretion of triacylglycerol and apoB was decreased following apoA-I incubation with ABCA1-expressing but not abca1^–/– hepatocytes.

These results support a major role for hepatocyte ABCA1 in generating a critical pool of HDL precursor particles that enhance further HDL generation and passive cholesterol mobilization in the periphery. The results also suggest that diversion of hepatocyte cholesterol into the "reverse" cholesterol transport pathway diminishes cholesterol availability for apoB-containing lipoprotein secretion by the liver.

Abbreviations: CE, cholesteryl ester; PC, phosphatidylcholine; SR-BI, scavenger receptor class B type I; TG, triacylglycerol

Supplementary key words ATP binding cassette transporter A1 • atherosclerosis • cholesterol • efflux • triacylglycerol • triglyceride

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