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Title: CAROTENOID TRANSPORT IS DECREASED AND EXPRESSION OF THE LIPID TRANSPORTERS SR-BI, NPC1L1, AND ABCA1 IS DOWNREGULATED IN CACO-2 CELLS TREATED WITH EZETIMIBE

Author
item DURING, ALEXANDRINE - JOHNS HOPKINS, BALTO, MD
item Dawson, Harry
item Harrison, Earl

Submitted to: Journal of Nutrition
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 7/5/2005
Publication Date: 10/4/2005
Citation: During, A., Dawson, H.D., Harrison, E.H. 2005. Carotenoid transport is decreased and expression of the lipid transporters sr-bi, npc1l1, and abca1 is downregulated in caco-2 cells treated with ezetimibe. Journal of Nutrition. 22:2305-2312.

Interpretive Summary: Carotenoids are essential nutrients as precursors of vitamin A. Their consumption is associated with beneficial health effects in humans, such as a decreased risk for certain types of cancer and for cardiovascular diseases. Therefore good knowledge about their intestinal absorption is essential. Until recently the intestinal absorption of carotenoids was thought to be done by passive diffusion. By using an in vitro cell culture system using Caco-2 cells, our previous data had suggested that intestinal carotenoid transport is a facilitated process perhaps mediated by specific transporters. In addition, several observations suggested that intestinal absorption of carotenoids and cholesterol may follow common mechanistic pathway(s). Therefore, the present study was conducted to investigate the effect of ezetimibe (an inhibitor of cholesterol absorption) on the cellular uptake and secretion of carotenoids in Caco-2 cells. Our data indicate that 1) ezetimibe is an inhibitor of the intestinal absorption of carotenoids, 2) the scavenger receptor of cholesterol (SR-BI) is involved in intestinal carotenoid transport, and 3) ezetimibe acts not only by interacting physically with cholesterol transporters as previously suggested, but also by down-regulating the gene expression of three proteins known to be involved in cholesterol transport in the enterocyte, the transporters SR-BI, NPC1L1 and ABCA1. The intestinal transport of carotenoid is thus a facilitated process ressembling that of cholesterol and, therefore, carotenoid trafficking in intestinal cells may also involve more than one transporter. More investigations are necessary to evaluate the contribution of each of the cholesterol transporters in the intestinal transport of carotenoids.

Technical Abstract: Data suggest that intestinal carotenoid absorption is a facilitated process. The present study was conducted to see if carotenoids and cholesterol share common pathways (transporters) for their intestinal absorption. Differentiated Caco-2 cells on membranes were incubated (16h) with a carotenoid +/- ezetimibe (an inhibitor of cholesterol transport) +/- antibodies against the receptors CD36 and SR-BI. Carotenoid transport in Caco-2 cells (cellular uptake plus secretion) was decreased by ezetimibe (10mg/L) as follows: beta-carotene ' alpha-carotene (50% inhibition) >> beta-cryptoxanthin ' lycopene (20%) >> lutein:zeaxanthin (1:1) (7%). Ezetimibe reduced cholesterol transport (31%), but not retinol transport. beta-Carotene transport was also inhibited by anti-SR-BI, but not by anti-CD36. Inhibitory effects of ezetimibe and anti-SR-BI on beta-carotene transport were additive, indicating that they may have different targets. Finally, differentiated Caco-2 cells treated with ezetimibe showed a significant decrease in mRNA expression for the surface receptors SR-BI, NPC1L1 and ABCA1 and for the nuclear receptors RARg, SREBP-1 and -2, and LXRb as assessed by real-time PCR analysis. The data indicate that 1) ezetimibe is an inhibitor of carotenoid transport; an effect decreasing with increasing polarity of the carotenoid molecule, 2) SR-BI is involved in carotenoid transport, and 3) ezetimibe may act, not only by interacting physically with cholesterol transporters as previously suggested, but also by down-regulating expression of these proteins. The cellular uptake and efflux of carotenoids, like that of cholesterol, likely involves more than one transporter.