{"id":6624,"date":"2026-04-01T10:36:51","date_gmt":"2026-04-01T10:36:51","guid":{"rendered":"https:\/\/www.proefschriftmaken.nl\/portfolio\/els-de-smet\/"},"modified":"2026-04-01T10:36:58","modified_gmt":"2026-04-01T10:36:58","slug":"els-de-smet","status":"publish","type":"us_portfolio","link":"https:\/\/www.proefschriftmaken.nl\/en\/portfolio\/els-de-smet\/","title":{"rendered":"Els De Smet"},"content":{"rendered":"","protected":false},"excerpt":{"rendered":"","protected":false},"author":8,"featured_media":6627,"comment_status":"closed","ping_status":"closed","template":"","meta":{"_acf_changed":false,"footnotes":""},"us_portfolio_category":[45],"class_list":["post-6624","us_portfolio","type-us_portfolio","status-publish","has-post-thumbnail","hentry","us_portfolio_category-new-template"],"acf":{"naam_van_het_proefschift":"Plant stanol esters","samenvatting":"Er is geen Nederlandse samenvatting beschikbaar. De Engelse samenvatting vind je <a href=\"https:\/\/www.proefschriftmaken.nl\/en\/portfolio\/els-de-smet\/\">hier<\/a>.","summary":"Cardiovascular diseases (CVD) are still the number one cause of death for men and women globally. Some risk factors for CVD (e.g. age and family history of early heart diseases) cannot be modified, but other can (e.g. smoking, hypertension, lack of physical activity, being overweight, unhealthy dietary habits and abnormal serum lipid and lipoprotein concentrations). Adopting a healthy lifestyle is therefore a cornerstone to decrease the risk for CVD. In this respect, functional foods, targeted to lower the atherogenic low-density lipoprotein cholesterol (LDL-C) concentrations, can be helpful. Functional foods contain (or lack) one or more components, thereby providing positive health effects beyond their traditional nutritional value. Plant stanol esters are an example of such components. They are incorporated into margarines and other food products, and reduce intestinal cholesterol absorption. The (intestinal) mechanism underlying the hypocholesterolemic effect of plant stanol esters is still unknown. Beside plant stanol esters, also other factors could be targeted to modulate intestinal cholesterol metabolism. In this context, animal studies have suggested that the gut microbiota plays a role in (intestinal) cholesterol metabolism. The aim of the studies described in this thesis was therefore to investigate the effects of plant stanol esters and amoxicillin, a moderate-spectrum antibiotic, which could change the composition of the gut microbiota, on (intestinal) lipid metabolism.\n\nIn the first study the acute effects of plant stanol esters on serum, intestinal and hepatic plant sterol and stanol concentrations was examined to gain more insight into the kinetics of plant stanol esters (chapter 3). In addition, acute effects on intestinal and hepatic expression profiles of genes involved in sterol metabolism were investigated. To reduce the impact of plant sterol and stanol already present in serum and tissues as much as possible, CS7BL\/6J mice were fed a plant sterol and stanol poor diet from weaning. At the age of 8 weeks, the mice received an oral gavage consisting of 0.25 mg cholesterol and of 50 mg plant stanols, which were provided as their fatty acids, dissolved in 500 \u00b5l refined plant sterol poor olive oil. The mice were fasted 2 hours before the gavage and sacrificed at 7 different time points post-gavage. The plant stanol concentrations increased in the intestine, but also in the liver 15 minutes after administration. This latter finding was highly unexpected, since it suggests that it takes only 15 minutes for plant stanol esters to be digested and absorbed into the enterocytes, incorporated and secreted as chylomicrons in the lymph, and taken up by the liver after entering the circulation. In addition, there was no clear change in serum plant stanol or cholesterol concentrations at this early time point. It could be possible that plant stanols reach the liver via the portal vein, independent of chylomicron formation. Therefore, a second study was performed to address the route of entrance into the liver. In this study, CS7BL\/6J mice were fed the same plant sterol and stanol poor diet from weaning. At the age of 8 weeks, mice were anesthetized and the ductus lymphaticus thoracicus was canulated proximal from the cisternae magnum via an abdominal approach. The mice in the control group were subjected to a sham operation, leaving the lymph circulation intact. They were given the same oral gavage, except that deuterium labelled plant stanols and cholesterol were used to follow concentrations and amounts of plant stanols and cholesterol from the gavage into the circulation and the tissues over time. The mice remained under anaesthesia until sacrificing at 6 different time points. The rapid hepatic appearance of deuterated-plant stanols was absent in the lymph-canulated mice. The intestinal uptake was, however, comparable between the lymph-canulated and the sham-operated mice. Altogether, this study showed that the appearance of plant stanols in the liver is lymph dependent. No deuterated-cholesterol was detected in the liver. This suggests that the rapid hepatic appearance was specific for plant stanols. Alternatively, it is possible that the detection limit for deuterated-cholesterol was too low due to dilution with cholesterol already present in the liver. The question still remains how and in which form (i.e. free or esterified), plant stanols enter the liver after 15 minutes without clear changes in serum concentrations.\n\nAnother finding was that changes in the expression profile of genes involved in sterol metabolism in the liver were opposite to those in the intestine. The increased intestinal expression of sterol regulatory element binding protein 2 (SREBP2) and its target genes can be explained by decreased intestinal cholesterol concentrations. In the liver, the expression of ABCG5\/ABCG8, two liver X receptor (LXR) target genes, was increased, but hardly changed in the intestine. This could be due to differences in desmosterol concentrations in the liver and the intestine, which act as an important regulator of LXR activation in macrophages. Finally, the pronounced increases in intestinal LDL receptor and proprotein convertase subtilisin\/kexin type 9 (PCSK9) expressions are suggestive for an enhanced clearance of cholesterol via the transintestinal cholesterol excretion (TICE). However, these speculations warrant further studies.\n\nTo study the acute effects of plant stanol esters on the expression profiles of genes from human enterocytes, 18 healthy normolipidemic volunteers received in a randomized double-blind placebo-controlled crossover design a shake enriched with or without 4 g plant stanol esters after an overnight fast (chapter 4). One week before the test, subjects were instructed to avoid products relatively rich in plant sterols and stanols. Five hours after consumption of the shake, intestinal biopsies were taken originating from the duodenum (around the Papil van Vater) and the jejunum (20 cm distal from the Papil van Vater). No changes in the expression profile of genes involved in sterol metabolism were found. However, immune-related T-cell pathways were downregulated in the jejunum. In humans with a disturbed immune response, plant stanol esters have already been observed to activate the immune system. In our study with healthy men, however, the immune response was dampened. The functional and physiological consequence of this effect deserves further investigation.\n\nIn that study, the acute effects of plant stanol esters on the postprandial lipid and lipoprotein profile were also examined (chapter 5). Furthermore, it was examined whether individual responses to longer-term consumption of plant stanol esters were related to results from the postprandial test. After an overnight fast, 18 healthy normolipidemic volunteers received a shake enriched with or without 4 g plant stanol esters. Blood samples were taken during the next 4 hours. Subjects receiving the shake with plant stanol esters during the postprandial test, continued with the margarine containing plant stanol esters for the next 3 weeks and vice-versa. The two intervention periods were separated by a washout period of four weeks. A positive correlation was found between the postprandial incremental area under the curve (iAUC) of glucose with changes in the concentration of total cholesterol, LDL-C, apoB100, total VLDL, small VLDL and IDL after 3 weeks consumption of a margarine enriched with plant stanol esters. This suggests that subjects with a more pronounced postprandial glucose response are less sensitive to the longer-term LDL-C-lowering effect of plant stanol ester consumption. However, there were no correlations with the iAUC of insulin and of the HOMA index. More research is needed which should focus on transcription factors associated with lipid, glucose and insulin metabolism such as SREBP2, SREBP-1c and carbohydrate-responsive element-binding protein (chREBP) to unravel the plant stanol ester-induced inhibition of intestinal cholesterol absorption.\n\nAfter the shake, serum total cholesterol concentrations decreased and those of triacylglycerol (TAG), glucose and insulin increased over time. These changes were comparable after consumption of the control or the plant stanol ester enriched shake. Also, the iAUC of serum TAG, insulin and plasma glucose were comparable after both meals. Changes in lipoprotein profiles were comparable after intakes of the plant stanol ester and control shakes.\n\nAs expected, three weeks consumption of a margarine enriched with plant stanol esters (3 g\/d) reduced serum concentrations of total cholesterol, LDL-C and apoB100. Serum HDL-C, TAG and apoA1 concentrations did not change. Furthermore, the number of total VLDL-CM, small VLDL and large LDL particles decreased compared to the control condition.\n\nAnimal studies have shown that the composition of the gut microbiota is related to lipid and lipoprotein metabolism (chapter 6). Therefore, effects of oral amoxicillin intake on lipid and glucose metabolism were examined in slightly hypercholesterolemic subjects. In a randomized, double-blind, placebo-controlled design, 74 subjects were assigned to use capsules containing placebo or amoxicillin during 1 week. Fasting blood samples were taken on days 1, 4, 8, 12 and 16. The last two time points were part of a washout period. Amoxicillin did not change serum concentrations of total cholesterol, LDL-C, TAG, C-reactive protein, glucose, insulin and the HOMA index. Body weight and blood pressure also did not change. However, a significant interaction term was found between amoxicillin treatment and baseline concentrations of HDL-C, TAG, glucose and the HOMA index. More specifically, amoxicillin decreased serum HDL-C concentrations more pronounced in subjects with higher serum HDL-C concentrations at baseline. For TAG, we found that the increase after amoxicillin intake was more pronounced in subjects with higher baseline values. After amoxicillin intake, glucose concentrations decreased in subjects with higher glucose concentrations at baseline. The HOMA index followed the same pattern as glucose. Finally, differences in HDL-C and TAG concentrations between the amoxicillin and placebo high-baseline groups tended to decrease during the washout period. A possible explanation for this rapid return might be changes on gene expression profiles. However, more research is needed to examine the effect of antibiotics on gene expression. Moreover, it is also interesting to investigate if amoxicillin intake changes the composition of the gut microbiota. Finally, it would be interesting to identify the specific microbiota responsible for the observed effects.","auteur":"Els De Smet","auteur_slug":"els-de-smet","publicatiedatum":"2 juli 2014","taal":"EN","url_flipbook":"https:\/\/ebook.proefschriftmaken.nl\/ebook\/elsdesmet?iframe=true","url_download_pdf":"","url_epub":"","ordernummer":"FTP-202604011033","isbn":"978-90-8891-909-1","doi_nummer":"","naam_universiteit":"Universiteit Maastricht","afbeeldingen":6628,"naam_student:":"","binnenwerk":"","universiteit":"Universiteit Maastricht","cover":"","afwerking":"","cover_afwerking":"","design":""},"_links":{"self":[{"href":"https:\/\/www.proefschriftmaken.nl\/en\/wp-json\/wp\/v2\/us_portfolio\/6624","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/www.proefschriftmaken.nl\/en\/wp-json\/wp\/v2\/us_portfolio"}],"about":[{"href":"https:\/\/www.proefschriftmaken.nl\/en\/wp-json\/wp\/v2\/types\/us_portfolio"}],"author":[{"embeddable":true,"href":"https:\/\/www.proefschriftmaken.nl\/en\/wp-json\/wp\/v2\/users\/8"}],"replies":[{"embeddable":true,"href":"https:\/\/www.proefschriftmaken.nl\/en\/wp-json\/wp\/v2\/comments?post=6624"}],"version-history":[{"count":1,"href":"https:\/\/www.proefschriftmaken.nl\/en\/wp-json\/wp\/v2\/us_portfolio\/6624\/revisions"}],"predecessor-version":[{"id":6625,"href":"https:\/\/www.proefschriftmaken.nl\/en\/wp-json\/wp\/v2\/us_portfolio\/6624\/revisions\/6625"}],"wp:featuredmedia":[{"embeddable":true,"href":"https:\/\/www.proefschriftmaken.nl\/en\/wp-json\/wp\/v2\/media\/6627"}],"wp:attachment":[{"href":"https:\/\/www.proefschriftmaken.nl\/en\/wp-json\/wp\/v2\/media?parent=6624"}],"wp:term":[{"taxonomy":"us_portfolio_category","embeddable":true,"href":"https:\/\/www.proefschriftmaken.nl\/en\/wp-json\/wp\/v2\/us_portfolio_category?post=6624"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}