Journal
JOURNAL OF NUTRITION
Volume 142, Issue 6, Pages 981-989Publisher
OXFORD UNIV PRESS
DOI: 10.3945/jn.111.157198
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- Deutsche Forschungsgemeinschaft [Lo 345/2-4]
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Phytosterol-enriched foods are increasingly marketed to lower cholesterol levels and atherosclerosis in the general population. Phytosterols reduce cholesterol absorption, but the molecular mechanism is controversial. We therefore investigated the phytosterol effects on cholesterol metabolism in human enterocyte, hepatocyte, and macrophage models relevant for sterol absorption, reverse transport, and excretion. Isomolar sitosterol (50 mu mol/L) was less effectively taken up by enterocytes than cholesterol but suppressed apical cholesterol uptake by 50% (P < 0.01) and basolateral secretion by two-thirds (P < 0.01) whether added in micelles or ethanol or complexed to cyclodextrin. In contrast, enterocytes handled nanomolar H-3-sitosterol similarly to cholesterol. Enterocytes selectively oxidized all sterols to 27-hydroxy- and 27-carboxy-sterols. Conversion rates were much lower for sitosterol (0.05 +/- 0.02 nmol/mg protein) and campesterol (0.48 +/- 0.10) compared with cholesterol (3.73 +/- 0.60) (P < 0.001). 27-Hydroxycholesterol (27OH-C) activated liver-X-receptor alpha (LXR alpha) (P < 0.01) and stimulated ATP-binding cassette transporter (ABC) A1 expression (P < 0.001) and basolateral systemic cholesterol secretion from enterocytes (P < 0.05). In co-incubations, phytosterols inhibited 27OH-C generation by sterol 27-hydroxylase (P < 0.001) and reduced LXR alpha-mediated ABCA1 expression (P < 0.01) and basolateral systemic cholesterol secretion. In contrast, ABCG8 transcription and apical sterol resecretion was unchanged by LXR alpha activation in human enterocytes. Exogenous LXR alpha agonists reverted sterol selectivity and phytosterol cholesterol interaction. Due to constitutive apical expression of ABCG5/G8 and LXR alpha-enhanced basolateral expression of ABCA1 in enterocytes, interference of phytosterols with the generation of the dominating LXR alpha-agonist 27OH-C blocks the self-priming component of cholesterol absorption. This local LXR alpha antagonism of dietary phytosterols contributes to sterol selectivity and reduces fractional cholesterol absorption and preloading of nascent HDL with dietary cholesterol. J. Nutr. 142: 981-989, 2012.
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