Increased intestinal ABCA1 expression contributes to the decrease in cholesterol absorption after plant stanol consumption

Abstract

The hypocholesterolemic effect of plant stanols is explained by a decreased intestinal cholesterol absorption due to a competition between plant stanols and cholesterol for incorporation into mixed micelles. Earlier we had suggested that plant stanols have a so far unknown action inside the enterocytes. The recent discovery of the involvement of ATP binding cassette (ABC) transporters in cholesterol absorption was a lead to further explore the hypocholesterolemic mechanism of plant stanols. We found that mixed micelles enriched with sitostanol or with cholesterol plus sitostanol were potent inducers of ABCA1 expression in caco-2 cells, an accepted model to study human intestinal lipoprotein metabolism. Based on these findings, we now hypothesize that plant stanols--and possibly plant sterols--increase ABCA1-mediated cholesterol efflux back into the intestinal lumen. We further hypothesize that intracellular levels of plant stanols are monitored by the same sensors (SREBP-2 and LXR) as those that monitor cholesterol. Consequently, increased plant stanol levels within the enterocyte activate cholesterol efflux through ABCA1- but not SREBP-2-mediated endogenous cholesterol synthesis even if intracellular cholesterol concentrations are lowered through consumption of plant stanols. If our hypothesis is correct, then the LXR pathway may be a target for dietary regulation of intestinal lipid metabolism.

Dose-response effects of different plant sterol sources in fat spreads on serum lipids and C-reactive protein and on the kinetic behavior of serum plant sterols

“…Modified PS and stanols have been shown to modify the cholesterol influx and efflux from cells by altering nuclear hormone receptor activity, although it is still under discussion whether such a direct effect on the gene level can be considered one of the key mechanisms of action of PS (Plat and Mensink, 2002;Kaneko et al, 2003;Plosch et al, 2004;Calpe-Berdiel et al, 2005). The potential effect on nuclear hormone receptors could also influence gene expression of inflammatory mediators such as iNOS, COX-2 and IL-6 (Joseph et al, 2003).…”

Effects of plant sterol and stanol ester consumption on lipid metabolism, antioxidant status and markers of oxidative stress, endothelial function and low-grade inflammation in patients on current statin treatment

“…The isolated cell pellet was taken up in 1500 ml Trizol (GIBCO, Invitrogen, Breda, The Netherlands) and immediately stored at -801C until further isolation according standard protocols. Following DNAse treatment (Promega Benelux B.V., Leiden, The Netherlands), cDNA was synthesized as described before (Plat and Mensink, 2002b). LDLreceptor mRNA expression was determined by real-time PCR.…”

“…The most likely explanation may be found in the primary location of the cholesterol-lowering effect, that is, the intestine. We have earlier hypothesized that the effect of plant sterols and stanols on cholesterol is because of the effects inside the enterocytes; most likely they increase cholesterol efflux back into the intestinal lumen (Plat and Mensink, 2002b). This can also occur in FH patients, as it does not involve LDL-receptor functioning.…”

Changes in Intestinal Gene Expression of Zebrafish (Danio rerio) Related to Sterol Uptake and Excretion upon β-Sitosterol Administration

“…For ABCA1, a study using Caco-2 cells reported that application of mixed micelles enriched with sitostanol enhanced ABCA1 expression [24]; ABCA1 expression would be more sensitive to sitosterol in mammals. Expression level of abca1 was significantly higher in the sitosterol-fed group, in comparison to the no-sterol and the cholesterol-fed groups in this study.…”