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Journal of Lipid Research, Vol. 49, 2605-2619, December 2008
Copyright © 2008 by American Society for Biochemistry and Molecular Biology

Origins of intestinal ABCA1-mediated HDL-cholesterol^*

F. Jeffrey Field¹, Kim Watt and Satya N. Mathur

Department of Internal Medicine, University of Iowa, Iowa City, IA 52242

^* This work was supported by National Institutes of Health Grant DK-067132.

Published, JLR Papers in Press, August 18, 2008.

¹ To whom correspondence should be addressed. e-mail: f-jeffrey-field{at}uiowa.edu

The origins of cholesterol utilized by intestinal ABCA1 were investigated in the human intestinal cell line Caco-2. Influx of apical membrane cholesterol increases ABCA1 mRNA and mass, resulting in enhanced efflux of HDL-cholesterol. Luminal (micellar) cholesterol and newly synthesized cholesterol are not transported directly to ABCA1 but reach the ABCA1 pool after incorporation into the apical membrane. Depleting the apical or the basolateral membrane of cholesterol by cyclodextrin attenuates the amount of cholesterol transported by ABCA1 without altering ABCA1 expression. Filipin added to the apical side but not the basal side attenuates ABCA1-mediated cholesterol efflux, suggesting that apical membrane "microdomains," or rafts, supply cholesterol for HDL. Preventing cholesterol esterification increases the amount of cholesterol available for HDL. Ezetimibe, a Niemann-Pick C1-like 1 protein inhibitor, does not alter ABCA1-mediated cholesterol efflux. U18666A and imipramine, agents that mimic cholesterol trafficking defects of Neimann-Pick type C disease, attenuate cholesterol efflux without altering ABCA1 expression; thus, intestinal NPC1 may facilitate cholesterol movement to ABCA1. ABCA1-mediated cholesterol efflux is independent of cholesterol synthesis. The results suggest that following incorporation into plasma membrane and rafts of the apical membrane, dietary/biliary and newly synthesized cholesterol contribute to the ABCA1 pool and HDL-cholesterol. NPC1 may have a role in this process.

Supplementary key words cholesterol trafficking • Caco-2 cells • cholesterol • lipoproteins • high density lipoproteins • ABCA1

Abbreviations: apoA-I, apolipoprotein A-I; LXR, liver X receptor; MTP, microsomal triglyceride transfer protein; NPC, Niemann-Pick type C; NPC1L1, Niemann-Pick C1-like 1 protein

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