Staff Publications

Staff Publications

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    'Staff publications' is the digital repository of Wageningen University & Research

    'Staff publications' contains references to publications authored by Wageningen University staff from 1976 onward.

    Publications authored by the staff of the Research Institutes are available from 1995 onwards.

    Full text documents are added when available. The database is updated daily and currently holds about 240,000 items, of which 72,000 in open access.

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    Industrial Trans Fatty Acids Stimulate SREBP2-Mediated Cholesterogenesis and Promote Non-Alcoholic Fatty Liver Disease
    Oteng, Antwi Boasiako ; Loregger, Anke ; Weeghel, Michel van; Zelcer, Noam ; Kersten, Sander - \ 2019
    Molecular Nutrition & Food Research 63 (2019)19. - ISSN 1613-4125
    cholesterogenesis - cholesterol metabolism - elaidate - non-alcoholic fatty liver disease - sterol regulatory element binding proteins

    Scope: The mechanisms underlying the deleterious effects of trans fatty acids on plasma cholesterol and non-alcoholic fatty liver disease (NAFLD) are unclear. Here, the aim is to investigate the molecular mechanisms of action of industrial trans fatty acids. Methods and results: Hepa1-6 hepatoma cells were incubated with elaidate, oleate, or palmitate. C57Bl/6 mice were fed diets rich in trans-unsaturated, cis-unsaturated, or saturated fatty acids. Transcriptomics analysis of Hepa1-6 cells shows that elaidate but not oleate or palmitate induces expression of genes involved in cholesterol biosynthesis. Induction of cholesterogenesis by elaidate is mediated by increased sterol regulatory element-binding protein 2 (SREBP2) activity and is dependent on SREBP cleavage–activating protein (SCAP), yet independent of liver-X receptor and ubiquitin regulatory X domain-containing protein 8. Elaidate decreases intracellular free cholesterol levels and represses the anticholesterogenic effect of exogenous cholesterol. In mice, the trans-unsaturated diet increases the ratio of liver to gonadal fat mass, steatosis, hepatic cholesterol levels, alanine aminotransferase activity, and fibrosis markers, suggesting enhanced NAFLD, compared to the cis-unsaturated and saturated diets. Conclusion: Elaidate induces cholesterogenesis in vitro by activating the SCAP–SREBP2 axis, likely by lowering intracellular free cholesterol and attenuating cholesterol-dependent repression of SCAP. This pathway potentially underlies the increase in liver cholesterol and NAFLD by industrial trans fatty acids.

    Glutaminolysis and Fumarate Accumulation Integrate Immunometabolic and Epigenetic Programs in Trained Immunity
    Arts, Rob J.W. ; Novakovic, Boris ; Horst, Rob ter; Carvalho, Agostinho ; Bekkering, Siroon ; Lachmandas, Ekta ; Rodrigues, Fernando ; Silvestre, Ricardo ; Cheng, Shih Chin ; Wang, Shuang Yin ; Habibi, Ehsan ; Gonçalves, Luís G. ; Mesquita, Inês ; Cunha, Cristina ; Laarhoven, Arjan van; Veerdonk, Frank L. van de; Williams, David L. ; Meer, Jos W.M. van der; Logie, Colin ; O'Neill, Luke A. ; Dinarello, Charles A. ; Riksen, Niels P. ; Crevel, Reinout van; Clish, Clary ; Notebaart, Richard A. ; Joosten, Leo A.B. ; Stunnenberg, Hendrik G. ; Xavier, Ramnik J. ; Netea, Mihai G. - \ 2016
    Cell Metabolism 24 (2016)6. - ISSN 1550-4131 - p. 807 - 819.
    cholesterol metabolism - epigenetics - glutamine metabolism - glycolysis - trained immunity

    Induction of trained immunity (innate immune memory) is mediated by activation of immune and metabolic pathways that result in epigenetic rewiring of cellular functional programs. Through network-level integration of transcriptomics and metabolomics data, we identify glycolysis, glutaminolysis, and the cholesterol synthesis pathway as indispensable for the induction of trained immunity by β-glucan in monocytes. Accumulation of fumarate, due to glutamine replenishment of the TCA cycle, integrates immune and metabolic circuits to induce monocyte epigenetic reprogramming by inhibiting KDM5 histone demethylases. Furthermore, fumarate itself induced an epigenetic program similar to β-glucan-induced trained immunity. In line with this, inhibition of glutaminolysis and cholesterol synthesis in mice reduced the induction of trained immunity by β-glucan. Identification of the metabolic pathways leading to induction of trained immunity contributes to our understanding of innate immune memory and opens new therapeutic avenues.

    A physiologically based kinetic model for the prediction of plasma cholesterol concentrations in mice and man
    Pas, N. van de - \ 2011
    Wageningen University. Promotor(en): Ivonne Rietjens; Ruud Woutersen, co-promotor(en): A.A. de Graaf. - [S.l.] : S.n. - ISBN 9789461731258
    cholesterolmetabolisme - klaring (plasma) - dierfysiologie - mannen - cholesterol metabolism - clearance - animal physiology - men

    An increased plasma cholesterol concentration is associated with increased risk of cardiovascular disease. However, individuals vary largely in their response to cholesterol lowering drugs and 40% of them, do not reach their cholesterol-lowering target. Development of novel therapies, for example combinations of existing drugs, can be accelerated by more mechanistic understanding of cholesterol metabolism. This understanding can be improved using computational models.

    This thesis describes the development, validation, and analysis of a physiologically based kinetic (PBK) model for the prediction of plasma cholesterol concentrations in humans. For this purpose, first a PBK model for the mouse was set up, calibrated and validated, using ensemble modeling. Then the mouse model was converted to a model for humans. It describes the 21 most influential physiological reactions affecting cholesterol concentrations in 8 pools, including liver, HDL, and non-HDL. The model was parameterized using literature data and validated using clinical data for human mutations and drug interventions, taken from literature.

    The model was applied to find properties that determine the individual response to drugs. The processes: hepatic cholesterol synthesis, peripheral cholesterol synthesis, and hepatic cholesterol esterification were major determinants of the non-HDL-C response to the cholesterol-lowering drug pravastatin.

    We conclude that plasma cholesterol concentrations and effects of genetic polymorphisms and drugs thereupon can be predicted in silico and thatPBK modeling can provide novel mechanistic insights.

    Genetic Variation in Bile Acid Metabolism: Implications for Lipoprotein Homeostasis
    Hofman, M.K. - \ 2005
    Wageningen University. Promotor(en): Evert Schouten; Frans Kok. - - 168
    cholesterolmetabolisme - galzuren - metabolisme - lipoproteïnen - homeostase - genetische variatie - genetica - atherosclerose - cholesterol metabolism - bile acids - metabolism - lipoproteins - homeostasis - genetic variation - genetics - atherosclerosis
    Genetic factors play an important role in the homeostasis of cholesterol in the human body. An important pathway for eliminating cholesterol from the body is to convert it into bile acids in the liver. The rate-limiting enzyme in this catabolism of cholesterol is CYP7A1. In the gene of CYP7A1, a sequence variation was found: the CYP7A1 A-278C polymorphism. We found that this polymorphism affects triglyceride concentrations in healthy individuals and cholesterol concentrations in patients with Hypertriglyceridemia. However, we found that this polymorphism probably plays no role in the response of serum lipid levels to diet. Interestingly, subjects with the genotype CC of the CYP7A1 A-278C polymorphism have an almost twice as high risk of a new clinical event, as compared to subjects with the genotype AA. In addition, subjects with the genotype CC display more progression of atherosclerosis. The results of this thesis contribute to the understanding of the role of variations in genes in cholesterol homeostasis in human.
    Elucidating the mechanism behind the lipid-raising effect of cafestol
    Boekschoten, M.V. - \ 2004
    Wageningen University. Promotor(en): M.B. Katan, co-promotor(en): Guido Hooiveld. - [S.I.] : S.n. - ISBN 9789085041139
    cafestol - koffie - cholesterolmetabolisme - lipiden - hart- en vaatstoornissen - gezondheid - cafestol - coffee - cholesterol metabolism - lipids - cardiovascular disorders - health
    The objective of this thesis was to identify genes that control the response of serum lipid levels to diet. To this end we used cafestol as model substance for a food component that affects serum lipids and therefore health. Cafestol is a cholesterol‑raising diterpene present in coffee beans and unfiltered coffee types.A possible explanation for the cholesterol-raising effect of cafestol is inhibition of bile acid synthesis. This is observed in APOE3Leiden mice upon treatment with cafestol. The nuclear receptors FXR and PXR are key regulators of genes involved in lipid and bile acid metabolism and detoxification.Both these nuclear receptorscan mediate inhibition of cholesterol 7a‑hydroxylase, the rate-limiting enzyme in bile acid synthesis. Therefore, we hypothesized that cafestol is able to activate FXR and/or PXR.We used promoter-reporter gene assays to show that cafestol interacts with FXR and PXR in vitro .This suggests that cafestol can regulate gene expression via these receptors. Indeed cafestol regulated several mRNA levels of target genes of FXR and PXR in livers of APOE3Leiden mice. For a number of target genes these effects were absent in livers of FXR and PXR knockout mice. This confirms that FXR and PXR are involved in the regulation of gene expression by cafestol. However, we could not confirm suppression of bile acid synthesis in humans. We measured plasma levels of7a‑hydroxy-4-cholesten-3-one, a marker for activity of cholesterol 7a‑hydroxylase, in volunteers that consumed coffee oil. Surprisingly, we observed an increase rather than a decrease in the level of 7a‑hydroxy‑4‑cholesten‑3‑one upon coffee oil treatment. In conclusion, it is likely that the interaction with FXR and PXR is at least partly responsible for the effect of cafestol on serum lipids in humans. However, the exact mechanism by which cafestol raises serum cholesterol remains to be elucidated. Elucidation of this mechanism will provide insight into how dietary components can affect serum lipid levels.
    Mechanistic studies on the lipid-raising coffee diterpenes cafestol and kahweol in monkeys, mice and man
    Roos, B. de - \ 2000
    Agricultural University. Promotor(en): M.B. Katan. - S.l. : S.n. - ISBN 9789058081728 - 120
    koffie - cholesterolmetabolisme - cafestol - diterpenen - bloedvetten - coffee - cholesterol metabolism - cafestol - diterpenes - blood lipids

    Cafestol and kahweol are lipid-raising diterpenes present in unfiltered coffee. The objective of this thesis was to study their lipid-raising action in man. Unravelling this action might lead to new insights into the regulation of serum cholesterol levels.

    We first studied the absorption and urinary excretion of cafestol and kahweol in eight ileostomy volunteers. About 70% of the consumed cafestol and kahweol was absorbed and thus available for raising serum lipids in humans. Only 1.2% of the diterpenes was subsequently excreted as a conjugate of glucuronic acid or sulphate in urine, suggestive for an extensive metabolism of coffee diterpenes.

    We then searched for an animal model to study the mechanism of action of cafestol and kahweol. In African green monkeys, both diterpenes raised total cholesterol less pronounced than in man. Unlike humans, the rise in cholesterol was predominantly due to a rise in HDL cholesterol rather than LDL cholesterol. In apolipoprotein E*3-Leiden mice, cafestol and kahweol increased total cholesterol with 61% after eight weeks of treatment. The increase in total cholesterol was mainly due to a rise in VLDL and IDL cholesterol. After three weeks of treatment, total cholesterol was increased due to suppression of bile acid synthesis, which caused a decreased expression of the LDL receptor. In addition, VLDL became enriched in cholesteryl esters.

    Two mechanistic studies were performed in healthy human subjects. Consumption of cafetiere (French-press) coffee increased CETP activity by 15% after 12 weeks of intervention. The increase in CETP activity clearly preceded the increase in LDL cholesterol. Cafestol increased serum triglycerides by an 80% increase in the production rate of VLDL 1 apolipoprotein B after two weeks of intervention. This resulted in an increased amount of VLDL 1 particles in the circulation. Cafestol did not change the composition of VLDL 1 . VLDL 2 became enriched with cholesteryl esters.

    In conclusion, cafestol first increases plasma triglycerides by increasing the production rate of VLDL 1 apolipoprotein B. The subsequent rise in LDL cholesterol might be due to suppression of bile acid synthesis, which probably leads to down-regulation of the LDL receptor and/or to an enrichment of VLDL 2 with cholesteryl esters. The mechanisms of action that raise plasma cholesterol and plasma triglycerides in humans might be regulated independently in the liver.

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