Background & Aims: In humans, cholesterol absorbed from the intestine contributes appreciably to serum cholesterol levels. We hypothesized that cholesterol thermodynamic activity (At) would predict bioavailability of cholesterol monomers in intestinal content, and that natural dietary phospholipids exhibiting high affinity for cholesterol would reduce its absorption. Methods: Cholesterol At was determined by measuring partitioning of monomeric cholesterol from aqueous solutions of taurocholate, cholesterol, and either milk sphingomyelin (MSM), dipalmitoyl phosphatidylcholine (DPPC), or egg yolk phosphatidylcholine (EYPC) into wafers of polymerized silicone. Cholesterol absorption from the same mixtures was tested with monolayers of Caco-2 cells. For in vivo absorption studies (employing male C57L/J mice), we used the fecal dual isotope method during dietary enrichment with MSM, DPPC, or EYPC at varying dose levels. Results: Cholesterol At values were reduced significantly in MSM- and DPPC-containing systems compared with EYPC and correlated positively with reduced uptake and esterification of cholesterol by Caco-2 cells. Mice fed chow absorbed 31.4% ± 6.9% (mean ± SEM) cholesterol, whereas enrichment with MSM or DPPC led to dose-dependent decreases in cholesterol absorption; even at 0.1% MSM, cholesterol absorption was reduced by 20.4% ± 15.4% (P < 0.05, n = 6). Conclusions: Different phospholipids have distinct effects on micellar cholesterol At, which predicts cholesterol uptake by enterocytes in vitro as well as in vivo. Natural phospholipids with high affinity for cholesterol, as evidenced particularly by sphingomyelin, decrease At and curtail intestinal cholesterol absorption.
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