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Journal of Lipid Research, Vol. 44, 1355-1363, July 2003
Copyright © 2003 by American Society for Biochemistry and Molecular Biology

Phosphatidylinositol promotes cholesterol transport and excretion

Jim W. Burgess^*, Jonathan Boucher, Tracey A-M. Neville^*, Patricia Rouillard^*, Chris Stamler, Susha Zachariah and Daniel L. Sparks^1,*,

^* Liponex, Inc., 1740 Woodroffe Ave, Building 400, Ottawa, Ontario, Canada, K2G 3R8
Lipoprotein and Atherosclerosis Research Group, University of Ottawa Heart Institute, 40 Ruskin Street, Ottawa, Ontario, Canada, K1Y 4W7

¹ To whom correspondence should be addressed. e-mail: dsparks{at}ottawaheart.ca

Administration of phosphatidylinositol (PI) to New Zealand white rabbits increases HDL negative charge and stimulates reverse cholesterol transport. Intravenously administered PI (10 mg/kg) associated almost exclusively with the HDL fraction in rabbits. PI promoted an increase in the hepatic uptake of plasma free cholesterol (FC) and a 21-fold increase in the biliary secretion of plasma-derived cholesterol. PI also increased cholesterol excretion into the feces by 2.5-fold. PI directly affects cellular cholesterol metabolism. In cholesterol-loaded macrophages, PI stimulated cholesterol mass efflux to lipid-poor reconstituted HDL. PI was about half as effective as cAMP at stimulating efflux, and the effects of cAMP and PI were additive. In cultured HepG2 cells, PI-enriched HDL also enhanced FC uptake from HDL by 3-fold and decreased cellular cholesterol synthesis and esterification. PI enrichment had no effect on the selective uptake of cholesterol esters or on the internalization of HDL particles. PI-dependent metabolic events were efficiently blocked by inhibitors of protein kinase C and the inositol signaling cascade.

The data suggest that HDL-PI acts via cell surface ATP binding cassette transporters and signaling pathways to regulate both cellular and intravascular cholesterol homeostasis.

Abbreviations: EMEM, minimum essential medium with Earle's salts; FC, free cholesterol; KBr, potassium bromide; POPC, 1-palmitoyl 2-oleoyl phosphatidylcholine; PI, phosphatidylinositol; RCT, reverse cholesterol transport

Supplementary key words atherosclerosis • bile • high density lipoprotein • hypercholesterolemia • lipid clearance • reverse cholesterol transport

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